Anti-atherosclerotic agents

ABSTRACT

This disclosure describes 2- or 3-[(unsaturated or cyclopropylated alkyl)amino]phenyl compounds and derivatives useful as hypolipidemic and antiatherosclerotic agents.

This is a continuation of application Ser. No. 85,652, filed Oct. 17,1979 now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and more particularly,is concerned with novel 2- or 3-(alkenylamino, cyclopropylalkylamino,and alkynylamino)phenyl compounds and derivatives which may berepresented by the following structural formula: ##STR1## wherein R' isa branched or unbranched mono- or poly-unsaturated or cyclopropylated C₃-C₂₂ alkyl group and can be represented by the formula: ##STR2## whereinR₂ and R₃ are the same or different and are hydrogen or a saturated orunsaturated C₁ to C₉ alkyl group;

Z is ##STR3## wherein D is selected from the group consisting ofhydrogen, hydroxy, loweralkyl, a loweralkoxy group unsubstituted orsubstituted with one or more moieties selected from the group consistingof hydroxy, carboxyl, carboloweralkoxy, carboxamido,N,N-diloweralkylcarboxamido, cyano, diloweralkylamino, piperazino orpolymethyleneimino (ring size 5-8) group; a benzyloxy groupunsubstituted or substituted with at least one halogen or carboxy group;a phenoxy moiety unsubstituted or substituted with at least one halogen,carboxy, carboloweralkoxy loweralkyl, carboxamido, loweralkoxy or cyanogroup; or a 3-pyridyloxy group unsubstituted or substituted with aloweralkyl group, halogen, cyano, carboxyl, carboloweralkoxy,loweralkoxy or hydroxy group; and loweralkyl bearing one or morecarboxy, carboloweralkoxy, carbamoyl, acyl, sulfinyl or sulfonyl groups;##STR4## wherein B is a saturated or unsaturated lower alkylene groupand E is selected from the group consisting of hydrogen, loweralkyl,loweralkoxyethyl, diloweralkylaminoethyl, (mono- orpolyhydroxy)loweralkyl, (mono- or polycarboxy)loweralkyl, (mono- orpolycarboxy)hydroxyloweralkyl, allyl, 2,3-epoxypropyl, substituted orunsubstituted (phenyl, benzyl or 3-pyridyl), pyridylmethyl, andtetrahydropyranyl; or ##STR5## wherein R₄ is selected from the groupconsisting of hydrogen, carboxyloweralkyl, carboalkoxyloweralkyl,lowerallkanoyl, loweralkanesulfonyl, arylsulfonyl, sodium sulfoloweralkyl, sulfo loweralkyl, loweralkenyl, loweralkynyl,phenylloweralkyl and -hydroxyloweralkyl; R₅ is selected from the groupconsisting of hydrogen, loweralkyl, hydroxy, loweralkoxy,haloloweralkyl, phenyl, carboxyphenyl, chlorophenyl, sodium sulfophenyl,pyridyl, pyridyl loweralkyl, (mono- and polyhydroxy)lower alkyl,ω-loweralkoxyloweralkyl, ω-di(loweralkyl)aminoloweralkyl,ω-piperidinoloweralkyl, ω-pyrrolidinohydroxylower alkyl, amino,loweralkanoylamino, loweralkanesulfonylamino, N-piperidyl,arylsulfonylamino, and 4-loweralkyl-1-piperazino; R₄ and R₅ takentogether with the associated nitrogen is selected from the groupconsisting of pyrrolidino, piperidino, morpholino, hexamethyleneimino,4-(loweralkyl)piperidino, 4-loweralkyl-1-piperazino, 4-phenylpiperazino,3-pyrrolinyl, Δ³ -piperidino, 4-(carboethoxy or carboxy)-3-thiazolidinyland 4-(carboethoxy)-3-oxazolidinyl; R₆ and R₇ are the same or differentand are selected from the group consisting of loweralkyl, (mono- andpolyhydroxy)loweralkyl, carboxyloweralkyl, sulfo loweralkyl, sodiumsulfo loweralkyl, and, when taken together, loweralkylene; R is selectedfrom the group consisting of hydrogen, or a group convertible in vivothereinto, such as methyl; carboxymethyl, acetyl, succinyl, 1-(sodiumsulfo)loweralkyl, 1-(sodium sulfo)polyhydroxyalkyl and 1,3-bis-(sodiumsulfo)-aralkyl; and wherein R₁ is a:

Formula (I-A): C₂ to C₂₁ E- or Z-alkenyl group unsubstituted orsubstituted with at least one lower alkyl group;

Formula (I-B): C₂ to C₂₀ alkynyl group unsubstituted or substituted withat least one methyl or ethyl group;

Formula (I-C): C₄ to C₂₀ alkyl group containing at least 2non-cumulative double bonds, said group being unsubstituted orsubstituted with at least one methyl or ethyl group;

Formula (I-D): C₃ to C₁₂ allenyl group unsubstituted or substituted withat least one methyl or ethyl group;

Formula (I-E): vinyl or C₃ to C₈ E- or Z-alkenyl group said vinyl oralkenyl group being unsubstituted or substituted with at least onemethyl group, and in this Formula I-E, R₂ is a vinyl or C₃ to C₈ E- orZ-alkenyl group unsubstituted or substituted with at least one methylgroup;

Formula (I-F): allyl or C₄ to C₈ E- or Z-alkenyl group said allyl oralkenyl group being substituted with at least one exo-(methylene,ethylidene, or isopropylidene), and either further unsubstituted orsubstituted with at least one methyl group;

Formula (I-G): vinyl or C₃ to C₈ E- or Z-alkenyl group substitutedbetween the nitrogen and the double bond with at least one loweralkenylsaid vinyl or alkenyl group being unsubstituted or substituted with atleast one methyl group;

Formula (I-H): vinyl C₃ to C₈ E- or Z-alkenyl group said vinyl oralkenyl group being unsubstituted or substituted with at least onemethyl and in this case, R₂ is a C₂ to C₉ alkynyl group unsubstituted orsubstituted with at least one methyl group;

Formula (I-I): C₄ to C₂₀ alkyl group containing at least onecarbon-carbon double bond and at least one carbon-carbon triple bondsaid group being unsubstituted or substituted with at least oneloweralkyl group;

or wherein R' is a:

Formula (I-J): group of the formula ##STR6## wherein R₁₁ is hydrogen ora C₁ to C₁₅ alkyl group unsubstituted or substituted with at least onemethyl group, R₁₀ is hydrogen or methyl and X is a bond or a C₁ to C₁₅branched or unbranched alkylene group unsubstituted or substituted withat least one methyl group;

and the pharmaceutically acceptable non-toxic acid addition and cationicsalts thereof.

The loweralkyl, loweralkenyl, loweralkynyl, loweralkoxy, loweralkanoyl,and loweralkanesulfonyl groups referred to herein contain 1 to 6 carbonatoms and are optionally unbranched or branched. The polyhydroxy andpolycarboxy groups referred to above contain 2 to 4 hydroxy or carboxygroups, respectively.

Preferred compounds of Formula I, including preferred compounds ofFormulas I-A through I-J are described below.

Preferred compounds of Formula I are those wherein Z is: ##STR7##wherein R₄ is a loweralkyl group substituted with at least one hydroxylgroup, allyl, propargyl, 2-sulfoethyl, --(CH₂)_(m) --COOR₉ wherein m is2-4 and R₉ is hydrogen or a loweralkyl group, ##STR8## wherein R₁₂ is aloweralkyl or aryl group, --SO₂ R₁₂, ##STR9## or a --NHSO₂ --R₁₂ group;n is one of the integers 4, 5 and 6 and R₁₃ is hydrogen or at least onemethyl group.

Also preferred are compounds of Formula I wherein Z is the moiety##STR10## wherein R₆ and R₇ are as previously defined.

Additionally preferred compounds of Formula I are those where D ishydroxy; a loweralkoxy group unsubstituted or substituted with one ormore carboxyl, hydroxyl, diloweralkylamino or polymethyleneimino (ringsize 5-8) groups; a benzyloxy or phenoxy group which is unsubstituted orsubstituted with at least one halogen or carboxyl group; or3-pyridyloxy.

Preferred compounds of Formula I are those wherein R is hydrogen, R₂ andR₃ are hydrogen or methyl.

Preferred compounds of Formula I-A are those where R₁ is a vinyl or C₃to C₂₁ E- or Z-alkenyl group said vinyl or alkenyl group beingunsubstituted or substituted with at least one methyl group; the mostpreferred compounds of Formula I-A are those wherein R₁ is a C₇ to C₁₅E- or Z-alkenyl group; and the most preferred of these are those inwhich R, R₂ and R₃ are hydrogen.

Preferred compounds of Formula I-B are those wherein R₂ and R₃ aremethyl; even more preferred compounds of Formula I-B are those whereinR₁ is C₂ to C₁₈ alkynyl and most preferred are those wherein R₁ is C₇ toC₁₈ alkynyl; and the most preferred of these are those wherein R, R₂ andR₃ are hydrogen.

Preferred compounds of Formula I-C are those wherein R₂ and R₃ arehydrogen or a loweralkyl group and those compounds of Formula I-Cwherein R₁ is C₄ to C₁₈ alkyl group containing at least twonon-cumulative double bonds; and most preferred of these are thosewherein R, R₂ and R₃ are hydrogen.

Preferred compounds of Formula I-D are those wherein R₂ is methyl; morepreferred compounds are those of Formula I-D wherein R₁ is a C₃ to C₁₂allenyl group and the other groups are as defined above; and the mostpreferred of these are those wherein R, R₂ and R₃ are hydrogen.

Preferred compounds of Formula I-E are those wherein R₁ is a C₂ or C₃alkenyl group; and the most preferred of these are those wherein R, R₂and R₃ are hydrogen.

Particularly preferred compounds of Formula I-F are those wherein R, R₂and R₃ are hydrogen.

Particularly preferred compounds of Formula I-G are those wherein R, R₂and R₃ are hydrogen.

Particularly preferred compounds of Formula I-H are those where R, R₂and R₃ are hydrogen; more preferred compounds are those where R₁ is aloweralkenyl or loweralkynyl group.

Particularly preferred compounds of Formula I-I are those wherein R₂ andR₃ are the same or different and each is hydrogen or methyl. Morepreferred compounds of Formula I-I are those wherein R₃ and/or R₂ ishydrogen; and other preferred compounds of Formula I-I are those whereinR₁ is a C₄ to C₁₃ alkyl group containing at least one carbon-carbondouble bond and at least one carbon-carbon triple bond. Most preferredcompounds of Formula I-I are those wherein R₁ is a C₆ to C₁₈ alkyl groupcontaining at least one carbon-carbon double bond and at least onecarbon-carbon triple bond.

Particularly preferred compounds of Formula I-J are those wherein R₁₀ ishydrogen. Most preferred compounds of Formula I-J are those wherein R,and R₁₀ are hydrogen.

Suitable keto-acids and keto-esters contemplated by the presentinvention are those in which the group D is selected from the groupconsisting of carboxymethyl; carboxyethyl; 2-carboethoxy-2-propyl;dicarboethoxymethyl; carboethoxyvinyl and the like. Suitable alkanoic,alkenoic and alkynoic acids and esters are those in which the radical Zis selected from the group consisting of 4-carboxybutyl;2-carboethoxyethyl; 2-carboxyvinyl, 2-carboethoxyethynyl, and the like.

The invention also pertains to novel compositions of matter useful asantiatherosclerotic agents and to methods of amelioratingatherosclerosis by counteracting hyperlipemia and arterial plaqueformation in mammals therewith; the active ingredients of saidcompositions of matter being the novel 2- or 3-[(unsaturated orcyclopropylated alkyl)amino]phenyl compounds of the present invention.These compounds may be utilized either as such or in the form of apharmaceutically acceptable salt with an organic or inorganic acid orbase. The invention also contemplates a method for lowering serum lipidsand for ameliorating atherosclerosis in mammals by the administration ofsaid compounds.

BACKGROUND OF THE INVENTION

Considerable effort has been directed in recent years to obtainsubstances useful in counteracting the consequences of hyperlipidemia, acondition involving elevated cholesterol, phospholipid and/ortriglyceride levels in the blood, and of hyperlipoproteinemia, involvingan imbalance of the lipo-proteins. The most serious condition associatedwith hyperlipidemia and hyperlipoproteinemia is atherosclerosis, a formof arteriosclerosis characterized by lipid accumulation and thickeningof the walls of both medium-sized and large arteries such as the aorta.Their walls are thereby weakened and the elasticity and effectiveinternal size of the arteries decreased. Atherosclerosis, the mostcommon cause of coronary artery disease, is of great medical importancesince it tends to occlude those arteries supplying blood to the heartmuscles and brain, thereby producing permanent damage to these organs.Such damage may lead to ischemic heart disease, congestive heartfailure, lifethreatening arrhythmias, senility, or stroke. Involvementof leg arteries may lead to gangrene and loss of the limb. It has beenknown for more than 100 years that cholesterol is a major component ofatherosclerotic lesions or plaques. Investigators have been trying todetermine the role of cholesterol in lesion initiation and developmentand also, more importantly, whether lesion formation can be prevented orreversed and enlargement of lesions be slowed or stopped. The earliestlesions are now known to be fatty streaks, largely of cholesterol, whichoften progress in stages to plaques containing cellular, fibrous andcalcified material in addition to the lipids.

The evidence that hyperlipidemia is one of the factors involved incoronary heart disease is very impressive. A most important studycarried out in Framingham, Mass. (Gordon and Verter, 1969) in over 5,000persons for more than 12 years established a correlation between highconcentrations of blood cholesterol and increased risk of heart attack.Although the causes of coronary artery disease are multiple, one of themost constant factors has been the elevated concentration of lipids inthe blood plasma. A combined elevation of cholesterol and triglycerideshave been shown (Carlson and Bottiger, 1972) to carry the highest riskof coronary heart disease. The majority of patients with ischemic heartdisease or peripheral vascular disease were found to havehyperlipoproteinemia, involving very low-density and/or low-densitylipoproteins (Lewis et al. 1974).

The reason for most treatment of hyperlipidemia or hyperlipoproteinemiais for arresting, reversing or preventing atherosclerosis. In the past,attempts have been made to lower the levels of cholesterol,phospholipids, and triglycerides in the blood by the oral feeding ofvarious substances which have been generally referred to in the art ashypolipidemic agents or hypocholesteremic adjuvants. Typical of suchsubstances are lecithin, pectin, cottonseed oil, and the mucilaginoussubstances listed in U.S. Pat. No. 3,148,114. In addition, severalsynthetic hypolipidemic agents are now available, namely, clofibrate,D-thyroxine, cholestyramine, and nicotinic acid [Levy and Frederickson,Postgraduate Medicine 47, 130 (1970)]. Clofibrate has the undesirableside-effect of causing hypertrophy of the liver in some patients.

The development of agents capable of reducing elevated blood lipids andof favorably altering blood-lipoprotein patterns is considered bymedical authorities to be extremely important for the treatment andprevention of atherosclerosis.

Related compounds are the subject of my copending applications Ser. No.884,673, filed Mar. 8, 1978 now U.S. Pat. No. 4,230,878 and Ser. No.8,641, filed Feb. 1, 1979, now U.S. Pat. No. 4,281,019.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are new and novel 2- or 3-[(unsaturatedor cyclopropylated alkyl)amino]phenyl compounds and derivatives ofFormula I (including Formulas I-A to I-J) which have useful biologicaland pharmacological properties. No hypolipidemic activity has beenreported in the literature for these compounds and they are different instructure from other hypolipidemic agents. The compounds of thisinvention lower serum-lipid concentrations and also minimize atheromaformation in the aorta. These substances also provide the oraladministration required for hypolipidemic agents, which patients usuallytake for many years. The novel compounds of this invention areadequately absorbed from the gastrointestinal tract.

We have now found that the compounds of the present invention can safelyand effectively lower both serum sterols and triglycerides inwarm-blooded mammals. Such actions on serum-lipid components areconsidered to be very useful in the treatment of atherosclerosis,especially in contrast to available drugs whose action is much morelimited. For some time it has been considered desirable to lowerserum-lipid levels and to correct lipoprotein imbalance in mammals as apreventive measure against atherosclerosis. The compounds of the presentinvention do not act by blocking late stages of cholesterol biosynthesisand thus do not produce accumulation of intermediates such asdesmosterol, as equally undesirable as cholesterol itself. Compoundswith the combination of therapeutically favorable characteristicspossessed by those of the present invention can be safely administeredto warm-blooded mammals for the treatment of hyperlipidemic andatherosclerotic states found in patients with or prone to heart attacks,to peripheral or cerebral vascular disease, and to stroke.

The novel compounds of the present invention are, in general, whitecrystalline solids having characteristic melting points and absorptionspectra. They are soluble in organic solvents such as lower alkanol,chloroform, benzene, dimethylformamide, and the like, but are generallynot very soluble in water. The novel compounds of the present invention,which are organic bases may be converted to their non-toxicacid-addition or cationic salts with a variety of pharmaceuticallyacceptable organic and inorganic salt-forming reagents. Thus,acid-addition salts may be formed by admixture of the organic free basein a neutral solvent with one or two equivalents of an acid such assulfuric, phosphoric, hydrochloric, hydrobromic, trifluoroacetic,citric, ascorbic, and the like. The compounds which contain acidicgroups form pharmaceutically acceptable cationic salts with organic orinorganic bases such as the alkali metal hydroxides, the alkaline earthmetal hydroxides, and the like. The sodium or potassium salts which areformed in solution in the course of hydrolysis of their esters can beisolated as the solid alkali metal salts by cooling. Where it isdesirable to purify a compound in the form of the acid, the salt isconveniently formed by treating its solution with exactly one equivalentof base and evaporation or lyophilization. Alkaline earth salts areprepared similarly, often using their acetate salts as a convenientlysoluble form. Organic base salts such as those of N-methylglucamine areprepared by dissolving equimolar amounts of the acid and the base in hotethanol or aqueous alcohols and cooling to crystallization.

The 2- or 3-[(unsaturated or cyclopropylated alkyl)amino]phenylcompounds of this invention are prepared by reaction of thecorresponding 2- or 3-aminophenyl compounds with suitable alkylatingagents, such as (unsaturated or cyclopropylated alkyl) halides,sulfates, tosylates, mesylates or trifliuoromethylsulfonates, with orwithout a solvent at 25°-150° C. Suitable solvents are lower alkanols,chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, diglyme,dimethylsulfoxide, acetonitrile, toluene, benzene,hexamethylphosphoramide and like solvents. The reaction may be carriedout with 2 equivalents of the unsubstituted amine compound or with onlyone equivalent and one equivalent of an unreactive organic base such asdiisopropylethylamine or an alkali carbonate or bicarbonate, or with acatalytic amount of copper powder when an appropriate halide is used asthe alkylating agent.

The N-acetyl-2- or 3-(substituted-amino)phenyl compounds are prepared byreaction of a corresponding 2- or 3-(acetylamino)phenyl compound with anappropriate (unsaturated or cyclopropylated alkyl) halide in thepresence of an equivalent of sodium hydride in an inert solvent such asN,N-dimethylformamide, N,N-dimethylacetamide or diglyme at 50°-150° C.The N-acetyl compounds are readily hydrolyzed to the acids in boilingaqueous ethanolic dilute alkali or acid.

Alternative methods of preparation are by reductive alkylation of a 2-or 3-aminophenyl compound which may also be generated in situ byreduction of 2- or 3-amino precursors such as a 2- or 3-nitro group andthe like, or by a borohydride reduction of a 2- or 3-(acylamino)phenylcompound. For example, a carbonylalkene such as an unsaturated ketone oraldehyde and ethyl 2-aminophenylacetate or methyl 2-aminobenzoate andthe like are reduced under 1-10 atmospheres of hydrogen using a suitablemetal catalyst or with a metal hydride such as sodium borohydrideforming the corresponding phenylacetic or benzoic acid and the like.Diborane reduction of 2- or 3-(cyclopropylalkanoylamino)phenyl compoundssuch as ethyl 2- or 3-(11-cyclohexylundecanoylamino)phenylacetate atroom temperature or above for 1-6 hours yields the corresponding 2- or3-(cyclopropylalkylamino)phenyl compounds such as ethyl3-(11-cyclopropylundecylamino)phenylacetate. The 2- or3-(cyclopropylalkanoylamino)phenyl compounds used in these reductionsare prepared by acylation of the appropriate 2 - or 3-aminophenylcompounds with suitable acylating agents, such as cyclopropylalkanoylhalides. To prepare the 2- or 3-(substituted-amino)phenyl alkenoic andalkynoic acids it is advantageous to form the correspondingalkylchloromide from the 2- or 3-(acylamino)phenyl compounds usingphosphorous oxychloride and base, and then reduce the alkylchloromidemoiety to an alkylamino group with sodium borohydride.

The 2- or 3-(substituted amino)phenyl compounds of this invention areoften prepared from the corresponding 2- or 3-aminophenyl compounds bythe sequence involving esterification of any carboxyl group present withethanol or methanol in the presence of boron trifluoride etherate,followed by alkylation of the amino function as described above. Thefree acids are then liberated by hydrolysis of the ester with aqueousalcoholic sodium hydroxide at 80° C. for 2-10 hours followed byacidification. The acids obtained by this procedure may be converted tothe corresponding cationic salts. For example, the sodium salt may beprepared by reaction of the benzoic acid with sodium hydroxide in amixture of ethanol and water. Alternatively, the free acids may beprepared by hydrolysis of the corresponding nitriles or various amides,imidates or oxazolines.

The 2- or 3-[(unsaturated or cyclopropylated alkyl)amino]phenylcompounds and derivatives are prepared by deacylation of thecorresponding 2- or 3-[(N-trifluoroacetyl)-(unsaturated orcyclopropylated alkyl)amino]phenyl compounds by reacting with an alkalihydroxide such as sodium or potassium hydroxide in a lower alkanol,water or an aqueous lower alkanol at 5° C. to 50° C. Alternatively,these compounds may be prepared by deacylation of the 2- or3-(N-carbo-t-butoxyalkenylamino)phenyl compounds with mineral acids suchas hydrochloric or hydrobromic acid, preferably in glacial acetic acidat 0° C. to 50° C. Also, they are prepared by removal of thecarbobenzyloxy protecting group from the anilino nitrogen atom by meansof mild catalytic hydrogenation or by treatment with a mineral acid suchas hydrobromic acid in glacial acetic acid.

With certain kinds of substrates for amide formation, it is necessary toform the alkali metal or strong organic base salts of these substratesin order to react them with the various aforementioned acylating formsof the 2- or 3-[(unsaturated or cyclopropylated alkyl)amino]benzoicacids. The aminoalkanecarboxylic and aminoalkanesulfonic acids arezwitterionic and must be converted to their cationic salts, suitably insitu. They may also be used in the form of their esters and thenhydrolyzed after amide formation. Certain substrates, which are neutrallike the carboxamides or slightly acidic like the alkane or arenesulfonamides, are converted to reactive salts by reaction with sodiumhydride or other basic reagents.

Alternatively the free acids may be prepared by hydrolysis of thecorresponding nitriles or various amides, imidates or oxazolines. Thecarboxylic acid moiety may also be generated by oxidation of thecorresponding aldehydes, acetophenones, benzyl alcohols, or toluenes,most often with the use of an amine-protecting group such astrifluoroacetyl or t-butyloxycarbonyl.

The imidates of the present invention are preferably prepared either byaddition of hydroxy compounds to the corresponding nitriles or byalkylation of the corresponding amides, suitably bearing a protectinggroup on the aromatic amino nitrogen atom in many cases. The addition ofalcohols and other hydroxy compounds is carried out under acid catalysiswithout additional solvent, if possible. Alkylation of the protonatedsubstituted aminoamide may be carried out or the aforementioned aminoprotecting groups can be employed. In some cases, simultaneousO-alkylation of the amide and N-alkylation of the aromatic amino moietycan be used to obtain a desired imidate. Intramolecular formation ofimidates results from 2-haloethyl and 3-halopropyl amides as well asfrom 2-hydroxyethyl and 3-hydroxypropyl amides when treated with acondensing agent.

Certain derivatives ##STR11## of the aminophenyl nitrogen atom areuseful for providing greater solubility, more uniform and reliableintestinal absorption, and for a certain degree of modification of thepharmacology of the compounds of the present invention. Some of thesederivatives can be converted to the corresponding N-H forms by theacidity of the stomach or the alkalinity of the small intestine. Othersare converted by metabolic processes. The methyl and carboxymethylderivatives and the like are prepared by the alkylation, reductivealkylation, and acylamino reduction methods above. Derivatives such asthe acetyl and succinyl compounds may be prepared using acetyl chloride,acetic anhydride, succinic anhydride, etc., in the presence of pyridine,triethylamine or the like at temperatures moderate enough to avoidacylation of the amide moiety. The 1-(sodium sulfo)alkyl derivatives areobtained by reaction of the 2- or 3-[(unsaturated or cyclopropylatedalkyl)amino]phenyl compound with sodium bisulfite and an aliphaticaldehyde, a polyhydroxyaldehyde such as glyceraldehyde or glucose, orcinnamaldehyde in a mixed organic aqueous medium. In the case ofcinnamaldehyde, the di-sulfonate salts result from addition of thebisulfite to the carbon-nitrogen double bond of the anil intermediate aswell as to the carbon-carbon double bond of cinnamaldehyde itself.

In certain cases, the unsaturation is introduced at a late stage of thepreparation, of the 2- or 3-(unsaturated alkylamino)phenyl compounds.For example, a 2- or 3-(ω-haloalkylamino)phenyl compound isdehydrohalogenated to the corresponding olefinic compound or,alternatively, it is converted to a Wittig trialkylphosphonium reagentand reacted with an aldehyde to yield a product with an internal doublebond. This ω-halo substrate can also be reacted with an alkylacetylenesodium or lithium salt to form the corresponding 2- or 3-alkynylaminoderivatives.

The carboxaldehydes of this invention may be prepared by several methodsamong which is alkylation of the corresponding acetals as describedabove followed by hydrolysis of the resulting 2- or3-(substituted-amino)phenyl compound to the desired aldehyde. Aldehydesmay also be prepared by reduction of the appropriate nitriles. Forexample, treatment of 2-(hex-3-enylamino)hydrocinnamonitrile withstannic chloride and anhydrous hydrogen chloride gas, followed byhydrolysis in hot water provides 2-(hex-3-enylamino)hydrocinnamaldehyde.These reductions are also conveniently carried out with hydrides such asdiisobutylaluminum hydride.

The α-substituted 2- or 3-(substituted-amino)acetophenones of theinvention are prepared by reaction of a derivative of the appropriatebenzoic acid, such as 2- or 3-(4-pentadecenylamino)phenylacetyl chloridehydrochloride, with two or more equivalents of the reactive salt of anacidic methylene compound, for example the sodium salt of diethylmalonate. Other benzoic acid derivatives are also suitable for thisreaction, such as an N-trifluoroacetyl or N-tert-butyl-oxycarbonyl acidchloride, or a methyl ester of the acid. In some cases the final step inthe preparation of the α-substituted 2- or3-(substituted-amino)acetophenone is the removal of thenitrogen-protecting group. In other cases, hydrolysis of one or more ofthe ester groups in the acylation product affords an unstablepolycarboxylic acid which undergoes decarboxylation to allow thepreparation of another acetophenone derivative. For example, thereaction of tert-butyl ethyl [3-(4-pentadecenylamino)benzoyl]malonatewith trifluoroacetic acid affords ethyl[3-(4-pentadecenylamino)benzoyl]acetate. In other cases, hydrolysis ofone or more of the ester groups allows the preparation of thecorresponding acid derivative. For example, the hydrolysis of ethyl [2-(hept-3-enylamino)benzoyl]acetate yields2-(hept-3-enylamino)benzoylacetic acid.

An alternative procedure for preparing certain 2- or3-(substituted-amino)acetophenones is alkylation of the corresponding 2-or 3-aminoacetophenone by the methods above. For Example, alkylation ofmethyl 3-(3-aminobenzoyl)propionate with undec-10-enyl bromide yieldsmethyl 3-[3-(undec-10-enylamino)benzoyl]propionate. The relatedcarboxylic acids are then obtained by hydrolysis. Certain of these acidsare particularly useful for the preparation of 2- or 3-(substitutedamino)phenylalkanoic acids by reduction. For example, the Clemmensen orWolff-Kishner reduction of 3-[3-(hex-3-enylamino)benzoyl]propionic acidyields 4-[3-(hex-3-enylamino)phenyl]butyric acid.

The 2- or 3-(substituted-amino)phenylalkenoic acids may be prepared bycondensation of the appropriate aldehydes or by dehydration of thecorresponding substituted phenylhydroxyalkanoic acids. For example,ethyl 5-[3-(undec-10-enylamino)phenyl]-2,4-pentadienoate is obtained bythe Wittig reaction of 3-(undec-10-enylamino)benzaldehyde with theWittig reagent, triethyl 4-phosphonocrotonate. Alternatively, thesealkenoic acids are obtained by heating a 2- or3-[N,N-disubstituted-amino]benzaldehyde and the like with the sodiumsalt of the carbanion of ethyl acetate or with a mixture of ethylacetate, acetic anhydride and potassium acetate. The second method isillustrated by dehydration of ethyl3-[2-(undec-10-enylamino)phenyl]-3-hydroxypropionate to thecorresponding cinnamate.

The acetylenic analogs are prepared by dehydrobromination of theside-chain vic-dibrominated alkanoic acid. For example,dehydrobromination of ethyl3-[3-(allylamino)phenyl]-2,3-dibromopropionate, its isomers or N-acylanalogs or of ethyl 3-[3-(allylamino)phenyl]-3-bromoacrylate yieldsethyl 3-(allylamino)phenylpropiolate. The acetylenic acids are alsoformed from (2- or 3-substituted-amino)phenylacetylene metal salts bycarboxylation with carbon dioxide. The 2- or3-(substituted-amino)phenylacetylenes are also prepared by N-acylatingwith t-butyl azidoformate followed by conversion to the lithiumacetylide salt and the subsequent reaction of the lithium salt withboron trifluoride etherate in tetrahydrofuran at -20° C. to formtris-[(2- or 3-substituted-amino)phenylethynyl]boranes. Thetetrahydrofuran solution of the borane is in turn reacted with ethyldiazoacetate, followed by water to yield ethyl 4-[(2- or3-substituted-amino)phenyl]butynoate.

The 2- or 3-(substituted-amino)phenylalkanoic acids, or esters are alsoprepared by catalytic reduction at 1 to 10 atmospheres of hydrogen ofthe corresponding alkenoic or alkynoic acid derivatives. The 2- or3-(substituted-amino)phenylalkenoic acids and derivatives are preparedby Friedel-Crafts acylation of the N-acyl-N-alkylanilines with theappropriate dicarboxylic acid anhydride or half acid chloride. The 2- or3-(substituted-amino)benzoylalkanoic acids or esters, obtained by thisand by other syntheses, may be converted to the corresponding 2- or3-(substituted-amino)phenylalkanoic acids by reduction with (a)hydrazine and alkali in diethylene glycol at 140° for 3 hours, (b) zincamalgam and ethanolic hydrochloric acid at 60° for 5 hours, (c) redphosphorus and hydriodic acid, or (d) ketalization with1,2-ethanedithiol followed by Raney nickel desulfurization. The amidesof these 2- or 3-(substitutedamino)phenylalkanoic acids are prepared byheating the corresponding 2- or 3-(substituted-amino)phenylalkyl ketoneswith aqueous alcoholic ammonium polysulfide followed by hydrolysis toyield the acids with the same number of carbon atoms as the ketone.These acids are also prepared by reacting a 2- or3-(N-butyloxycarbonyl-N-substituted-amino)phenylmagnesium halide with2-(3-halopropyl)-2-oxazolines, followed by mild acid removal of2-oxazolinyl and t-butoxycarbonyl protecting groups. Similarly, theabove Grignard reagent can be reacted with3-bromotriethylorthopropionate in the presence ofdilithium-tetrachlorocuprate to yield the desired acids after removal ofthe protecting groups from the amino and carboxyl groups.

The novel 2- or 3-(substituted-amino)phenyl compounds of the presentinvention are not only potent hypolipidemic agents but also prevent ordiminish the formation or enlargement of arterial plaques in mammalswhen administered in amounts ranging from about one mg. to about 250 mg.per kilogram of body weight per day. A preferred dosage regimen foroptimum results would be from about 5 mg. to about 100 mg. per kilogramof body weight per day, and such dosage units are employed that a totalof from about 0.35 grams to about 7.0 grams of the active compound, fora subject of about 70 kg. of body weight, are administered in a 24 hourperiod. This dosage regimen may be adjusted to provide the optimumtherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A decidedpractical advantage of this invention is that the active compound may beadministered in a convenient manner by the oral route. The compounds ofthe present invention exert a more powerful hypocholesteremic andantiatherosclerotic effect than the aforementioned adjuvants andsynthetic medicaments. It is not known how these novel compounds operatein the blood serum and no theory of why these compounds so operate isadvanced. It is not intended that the present invention should belimited to any particular mechanism of action of lowering serum lipidsor of ameliorating atherosclerosis, or be limited to compounds acting byonly one mechanism.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of ingestible tablets, buccal tablets, troches,capsules, elixirs, suspensions, syrups, wafers, and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage of the compositions and preparations may, ofcourse, be varied and may conveniently be between about 2 to about 60%of the weight of the unit. The amount of active ingredient in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage-unit form containsbetween about 50 and 250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate, a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When thedosage-unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance, tablets, pills or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye, and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage-unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active ingredients may be incorporated intosustained-release preparations and formulations.

The invention will be described in greater detail in conjunction withthe following specific Examples.

EXAMPLE 1 Preparation of 3-(allylamino)phenylacetic acid (Method A)

To a solution of 18.2 g. of ethyl 3-aminophenylacetate in 100 ml. ofdimethylformamide is added a solution of 4.7 ml. of allyl bromide in 60ml. of dimethylformamide. The solution is heated at 60° C. for 5 hoursand then cooled and partitioned between diethyl ether and water. Thecombined ether phases are washed with water, dried over magnesiumsulfate, and concentrated in vacuo to provide 16.5 g. of a semi-solid. Aportion (6 g.) is absorbed onto 30 g. of silica gel and chromatographedon 475 g. of silica gel to provide ester.

A mixture of the ester, 22.0 g. of potassium hydroxide and 200 ml. ofethanol-water (8:1) is stirred under reflux for 6 hours. Concentratedhydrochloric acid (about 80 ml.) is added to the warm mixture andcooling and dilution with water affords a white solid which is collectedby filtration and recrystallized from ethanol to yield the product as awhite solid.

EXAMPLE 2 Preparation of 3-(1-pentadeca-4,14-dienylamino)benzoic acid(Method B)

To a solution of 4,14-pentadecadien-1-ol (15.0 g.) and triethylamine (14ml.) in dry methylene chloride (320 ml.) at -8° C. is addedmethanesulfonylchloride (5.73 ml.), dropwise. The reaction mixture isstirred at -10° C. for 30 minutes and then diluted with methylenechloride, extracted with ice-water (250 ml.); followed by cold 10%hydrochloric acid (200 m.); cold saturated sodium bicarbonate (200 ml.)and cold brine (200 ml.). The organic phase is dried over magnesiumsulfate and the solvent removed in vacuo to provide the crude mesylate.

A solution of 18.1 g. of the above mesylate and 19.8 g. of ethyl3-aminobenzoate in hexamethylphosphoramide is heated at 120° C. for 20hours. After cooling, the reaction mixture is diluted with 30 ml. ofethanol:water (1:1) (30 ml.) and chilled. More ethanol is added and thesolid material is collected. This solid is recrystallized twice fromethanol to provide the ester.

A mixture of the ester, 22.0 g. of potassium hydroxide and 200 ml. ofethanol-water (8:1) is stirred under reflux for 6 hours. Concentratedhydrochloric acid (about 80 ml.) is added to the warm mixture andcooling and dilution with water affords a white solid which is collectedby filtration and recrystallized from ethanol to yield the product as awhite solid.

EXAMPLES 3-317

Treatment of the indicated halide or carbinol starting material setforth in Table I below by the indicated method is productive of theproduct listed in the table. Reference B in Tables I and II is J. Med.Chem. 11, 1190 (1968).

                  TABLE I                                                         ______________________________________                                        Ex-                                                                           am-                  Meth-                                                    ple  Starting Material                                                                             od      Product                                          ______________________________________                                         3   E-4-tetradecenol                                                                              B       2-(E-1-tetradec-                                                              4-enylamino)-                                                                 phenylacetic acid                                 4   Z-9-octadecen-1-ol                                                                            B       3-(Z-1-octadec-9-                                                             enylamino)benzoic                                                             acid                                              5   E-4-pentadecen-1-ol                                                                           B       2-(E-1-pentadec-4-                                                            enylamino)phenyl-                                                             acetic acid                                       6   3-chloro-2,4,4-tri-                                                                           A       3-[3-(2,4,4-tri-                                      methyl-1-pentene        methyl)-penty-1-                                      Chem. Abst. 72,         enylamino]benzoic                                     111081h                 acid                                              7   3-bromo-3-isoprop-                                                                            A       2-[3-(3-isopropyl-                                    yl-4-methyl-1-pent-     4-methyl)pent-1-                                      ene Chem. Abst. 54,     enyl-amino]phenyl-                                    4355a                   acetic acid                                       8   4-bromo-2-heptene                                                                             A       3-(4-hept-2-enyl-                                     Chem. Abst. 70,         amino)benzoic acid                                    67482x                                                                    9   4-bromo-2,4-dimeth-                                                                           A       2-[4-(2,4-dimethyl-                                   yl-2-hexene             hex-2-enyl)amino]-                                                            phenylacetic acid                                 10  5-chloro-3,5-di-                                                                              A       3-[5-(3,5-dimethyl-                                   methyl-3-heptene        hept-3-enyl)amino]-                                   Chem. Abst. 54,         benzoic acid                                          1256e                                                                     11  z-1-hydroxy-2-hexa-                                                                           B       2-(Z-1-hexadec-2-                                     decene Ref. B           enylamino)phenyl-                                                             acetic acid                                       12  E-1-hydroxy-2-hexa                                                                            B       3-(E-1-hexadec-2-                                     decene Ref. B           enylamino)phenyl-                                                             acetic acid                                       13  1-bromo-4-methyl-                                                                             A       2-[1-(4-methylhept-                                   3-heptene Chem.         3-enyl)amino] benzoic                                 Abst. 71, 102020q       acid                                              14  1-bromo-4-methyl-3-                                                                           A       3-[1-(4-methynon-3-                                   none Chem. Abst.        enyl)amino]phenyl                                     71, 101399h             acetic acid                                       15  E-7-bromo-3-hept-                                                                             A       2-(1-hept-4-enyl-                                     ene Chem. Abst. 74,     amino)benzoic acid                                    99419f                                                                    16  1-bromo-5,9-dimeth-                                                                           A       3-[1-(5,9-dimethyl-                                   yl-4-decene Chem.       dec-4-enyl)amino]-                                    Abst. 51, 8699g         phenylacetic acid                                 17  1-methanesulfonyl-                                                                            B       2-(1-tetradec-                                        oxy-4-tetradecene       4-enylamino)phenyl-                                   Ref. B.                 acetic acid                                       18  1-methanesulfonyl-                                                                            B       3-(1-hexadec-                                         oxy-4-hexadecene        4-enylamino)benzoic                                   Ref. B.                 acid                                              19  6-bromo-1-hexene                                                                              A       2-(1-hex-5-enyl-                                      Chem. Abst. 66,         amino)phenylacetic                                    2142j                   acid                                              20  6-bromo-2-methyl-                                                                             A       3-[1-(5-methylhex-                                    1-hexene Chem.          5-enyl)amino]benzoic                                  Abst. 75, 109624f       acid                                              21  6-chloro-1-heptene-                                                                           A       2-(2-hept-6-enyl-                                     Chem. Abst. 72,         amino)phenylacetic                                    31877g                  acid                                              22  6-bromo-2-methyl-2-                                                                           A       3-[2-(2,6-dimethyl-                                   heptene Chem. Abst.     hept-5-enyl)amino]-                                   54, 13166f              benzoic acid                                      23  7-chloro-2-octene                                                                             A       2-(2-oct-6-enyl-                                      Chem. Abst. 75,         amino)phenylacetic                                    129245m                 acid                                              24  E-1-chloro-4-nonene                                                                           A       2-(E-1-non-5-enyl-                                    Chem. Abst. 67,         amino)benzoic acid                                    32294g                                                                    25  7-bromo-1-heptene                                                                             A       3-(1-hept-6-enyl-                                                             amino)phenylacetic                                                            acid                                              26  7-chloro-1-octene                                                                             A       2-(2-oct-7-enyl-                                      Chem. Abst. 75,         amino)benzoic acid                                    29245m                                                                    27  6-bromo-6-methyl-                                                                             A       3-[1-(2-methylhept-                                   1-heptene Chem.         6-enyl)amino]phenyl-                                  Abst. 66, 94482w        acetic acid                                       28  6-chloro-6-methyl-                                                                            A       2-[1-(6-methylhept-                                   1-heptene Chem.         6-enyl)amino]benzoic                                  Abst. 75, 129245        acid                                              29  E-8-bromo-2-octene                                                                            A       3-(1-oct-6-enyl-                                      Chem. Abst. 74, 99419f  amino)phenyl-                                                                 acetic acid                                       30  8-bromo-2,6-dimeth-                                                                           A       2-[1-(3,7-dimethyl-                                   yl-2-octene Chem.       oct-6-enyl)amino]-                                    Abst. 72, 90573c        benzoic acid                                      31  11-bromo-5-undecene-                                                                          A       3-(1-undec-6-enyl-                                    Chem. Abst. 67, 73101b  amino)phenylacetic                                                            acid                                              32  8-bromo-1-octene                                                                              A       2-(1-oct-7-enyl-                                      Chem. Abst. 70,         amino)benzoic acid                                    10990g                                                                    33  R-8-iodo-7-meth-                                                                              A       3-[R-(2-methyloct-                                    yl-1-octene Chem.       7-enyl)amino]phenyl-                                  Abst. 74, 12573e        acetic acid                                       34  1-chloro-7-tetra-                                                                             A       2-(1-tetradec-7-                                      decene Chem. Abst.      enylamino)benzoic                                     54, 22461h              acid                                              35  9-chloro-1-nonene                                                                             A       3-(1-non-8-enyl-                                      Chem. Abst. 70,         amino)phenylacetic                                    114490k                 acid                                              36  1-bromo-8-hepta-                                                                              A       2-(1-heptadec-8-                                      decene Chem. Abst.      enylamino)benzoic                                     52, 249d                acid                                              37  E-1-bromo-9-octa-                                                                             A       2-(E-1-octadec-9-                                     decene Chem. Abst.      enylamino)phenyl-                                     70, 46779j              acetic acid                                       38  Z-1-bromo-9-octa-                                                                             A       3-(Z-1-octadec-9-                                     decene Chem. Abst.      enylamino)benzoic                                     70, 46779j              acid                                              39  11-chloro-1-undec-                                                                            A       2-(1-undec-10-enyl-                                   ene Chem. Abst. 66,     amino)phenylacetic                                    P19046d                 acid                                              40  12-iodo-3,7,11-tri-                                                                           A       3-[1-(2,6,10-tri-                                     methyl 1-dodecene       methyldodec-11-                                                               enyl)amino]benzoic                                                            acid                                              41  13-bromo-1-tridec-                                                                            A       2-(1-tridec-12-                                       ene Chem. Abst. 67,     enylamino)phenyl-                                     43348v                  acetic acid                                       42  22-bromo-9-docos-                                                                             A       3-[1-(2-methyl-                                       ene Chem. Abst.         hept-6-enyl)amino]-                                   73, 44976j              benzoic acid                                      43  16-methanesulfonyloxy-                                                                        B       2-(1-hexadec-15-                                      1-hexadecene            enylamino)phenyl-                                     Ref. B.                 acetic acid                                       44  propargyl alcohol                                                                             B       3-(1-prop-2-ynyl-                                                             amino)benzoic acid                                45  3-chloro-1-butyne                                                                             A       2-(2-but-3-ynyl-                                                              amino)phenylacetic                                                            acid                                              46  3-chloro-3-methyl-                                                                            A       3-[3-(3-methylnon-                                    nonyne Chem. Abst.      1-ynyl)amino]benzoic                                  55, 22090i              acid                                              47  3-bromo-1-penta-                                                                              A       2-(3-pentadec-1-                                      decyne Chem. Abst.      nylamino)phenyl-                                      53, 21638c              acetic acid                                       48  1-octyn-3-ol Chem.                                                                            B       3-(3-oct-1-ynyl-                                      Abst. 66 85410n         amino)benzoic acid                                49  3,7,11,15-tetra-                                                                              B       2-[3-(3,7,11,15-                                      methyl-1-hexadecyn-     tetramethylhexadec-                                   3-ol                    1-ynyl)amino]-                                                                benzoic acid                                      50  2-butyn-1-ol    B       3-(1-but-2-ynyl-                                                              amino)phenylacetic                                                            acid                                              51  4-hexyn-3-ol    B       2-(3-hex-4-ynyl-                                                              amino)benzoic acid                                52  2-methyl-3-pentyn-                                                                            B       3-[2-(2-methylpent-                                   2-ol Chem. Abst.        3-ynyl)amino]phenyl-                                  69, 10496e              acetic acid                                       53  2-octyn-1-ol    B       2-(1-oct-3-ynyl-                                                              amino)benzoic acid                                54  4-decyn-3-ol    B       3-(3-dec-4-ynyl-                                      Chem. Abst. 69,         amino)phenylacetic                                    P4630s                  acid                                              55  1-bromo-2-do-   A       2-[1-dodec-2-ynyl-                                    decyne Chem.            amino)benzoic acid                                    Abst. 28, 40345                                                           56  1-methanesulfonyl-                                                                            B       3-(1-pentadec-                                        oxy-2-pentadecyne       2-ynylamino)phenyl-                                   J. Med. Chem 19,        acetic acid                                           946 (1977)                                                                57  3-butyne-1-ol   B       2-(1-but-3-ynyl-                                      Chem. Abst.             amino)benzoic acid                                    66, P2319a                                                                58  1-undecyn-4-ol  B       3-(4-undec-1-ynyl-                                    Chem. Abst. 70,         amino)phenylacetic                                    3219j                   acid                                              59  2-methyl-4-pentyn-                                                                            B       2-[2-(2-methylpent-                                   2-ol Chem. Abst.        4-ynyl)amino]-                                        68, 12200g              benzoic acid                                      60  4-pentyn-2-ol   B       3-(2-pent-4-ynyl-                                     Chem. Abst. 64,         amino)phenylacetic                                    13537e                  acid                                              61  3-pentyl-1-ol   B       2-(1-hex-3-ynyl-                                                              amino)phenylacetic                                                            acid                                              62  4-hexyn-2-ol    B       3-(2-hex-4-ynyl-                                                              amino)benzoic acid                                63  2-methyl-3-pentyn-                                                                            B       2-[1-(2-methyl-                                       1-ol Chem. Abst.        3-pent-3-ynyl)-                                       66, 115242k             amino]phenylacetic                                                            acid                                              64  2-(1-propynyl)-1-                                                                             B       3-[2-(1-propynl-                                      heptanol Chem.          heptyl)amino]-                                        66, 115242k             benzoic acid                                      65  2-methyl-4-nonyn                                                                              B       2-[2-(2-methylnon-                                    2-ol Chem. Abst.        4-ynyl)amino]                                         68, 104593r             phenylacetic acid                                 66  2-methyl-3-nonyn-                                                                             B       3-[1-(2-methylnon-3-                                  1-ol Chem. Abst.        ynyl)amino]benzoic                                    66, 115242k             acid                                              67  3-nonyn-1-ol    B       2-(1-non-3-ynyl-                                      Chem Abst. 75           amino)phenylacetic                                    5165r                   acid                                              68  2-methyl-3-decyn-                                                                             B       3-[1-(2-methyldec-                                    1-ol Chem. Abst.        3-ynyl)amino]-                                        66, 115242k             benzoic acid                                      69  5-chloro-1-pentyne                                                                            A       2-(1-pent-4-ynyl-                                                             amino)phenylacetic                                                            acid                                              70  4-hexyn-1-ol    B       3-(1-hex-4-ynyl-                                      Chem. Abst. 74,         amino)benzoic acid                                    9800w                                                                     71  1-chloro-4-nonyne                                                                             A       2-(1-non-4-ynyl-                                                              amino)phenylacetic                                                            acid                                              72  1-chloro-4-tri- A       3-(1-pentadec-                                        decyne Chem.            2-ynylamino)benzoic                                   Abst. 32, 7426.sup.3    acid                                              73  1-chloro-4-hexa-                                                                              A       2-(1-hexadec-4-ynyl-                                  decyne                  amino)benzoic acid                                74  5-hexyn-1-ol    B       3-(1-hex-5-ynyl-                                      Chem. Abst. 74,         amino)phenylacetic                                    9800w                   acid                                              75  6-octyn-2-ol    B       2-[2-(2-methyloct-                                    Chem. Abst.             6-ynyl)amino]benzoic                                  71, 60300y              acid                                              76  1-iodo-5-decyne A       3-(1-dec-5-ynyl-                                      Chem. Abst. 51,         amino)phenylacetic                                    12817f                  acid                                              77  5-tetradecyn-1-ol                                                                             B       2-(1-tetradec-                                        Chem. Abst. 71,         5-ynylamino)benzoic                                   12053k                  acid                                              78  5-octadecyn-1-ol                                                                              B       3-(1-octadec-5-ynyl-                                  Chem. Abst. 72,         amino)phenylacetic                                    42686v                  acid                                              79  6-octadecyn-1-ol                                                                              B       2-(1-octadec-6-ynyl-                                  Chem. Abst.             amino)benzoic acid                                    72, 42686v                                                                80  10-chloro-3-decyne                                                                            A       3-(1-dec-7-ynylamino)-                                Chem. Abst.             phenylacetic acid                                     67, 108147a                                                               81  1-chloro-7-tetra-                                                                             A       2-(1-tetradec-                                        decyne Chem.            7-ynylamino)benzoic                                   Abst. 54, 2461e         acid                                              82  7-hexadecyn-1-ol                                                                              B       3-(1-hexadec-7-ynyl-                                  Chem. Abst.             amino)phenylacetic                                    71, 19554w              acid                                              83  7-octadecyn-1-ol                                                                              B       2-(1-octadec-7-ynyl-                                  Chem. Abst. 67,         amino)benzoic acid                                    81784w                                                                    84  8-octadecyn-1-ol                                                                              B       3-(1-octadec-8-ynyl-                                  Chem. Abst. 72,         amino)phenylacetic                                                            acid                                              85  9-decyn-1-ol    B       2-(1-octadec-9-ynyl-                                  Chem. Abst. 67,         amino)benzoic acid                                    81787s                                                                    86  10-octadecyn-1-ol                                                                             B       2-(1-octadec-                                         Chem. Abst. 67,         10-ynylamino)phenyl-                                  81787s                  acetic acid                                       87  4-nonyn-1-ol    B       3-(1-non-4-ynylamino)-                                Chem. Abst. 67,         benzoic acid                                      88  11-dodecyn-1-ol B       2-(1-dodec-11-ynyl-                                   Chem. Abst.             amino)phenylacetic                                    68, 39015n              acid                                              89  11-tetrdecyn-1-ol                                                                             B       3-(1-tetradec-11-ynyl-                                Chem. Abst.             amino)benzoic acid                                    75, 16972u                                                                90  11-tridecyn-1-ol                                                                              B       2-(1-tridec-11-ynyl-                                  Chem. Abst. 75,         amino)phenylacetic                                    1679u                   acid                                              91  16-bromo-5-hexa-                                                                              A       3-(1-hexadec-11-ynyl-                                 decyne Chem. Abst.      amino)benzoic acid                                    68, 39015n                                                                92  12-octadecyn-1-ol                                                                             B       2-(1-octadec-                                         Chem. Abst. 68,         12-ynylamino)-                                        39015n                  phenylacetic acid                                 93  12-octadecyn-1-ol                                                                             B       3-(1-octadec-                                         Chem. Abst.             12-ynylamino)-                                        72,4286v                benzoic acid                                      94  13-tetradecyn-1-ol                                                                            B       2-(1-tetradec-                                        Chem. Abst.             13-ynylamino)phenyl-                                  68, 39015n              acetic acid                                       95  14-pentadecyn-1-ol                                                                            B       3-(1-pentadec-                                        Chem. Abst.             14-ynylamino)benzoic                                  68, 39015n              acid                                              96  5,7-octadien-4-ol                                                                             B       2-(4-octa-5,7-di-                                     Chem. Abst. 72,         enylamino)phenyl-                                     42686v                  acetic acid                                       97  4-ethyl-3,5-hexa-                                                                             B       3-[2-(4-ethylhexa-                                    decadien-2-ol           3-5-dienyl)amino]-                                    Chem. Abst. 70          benzoic acid                                          20116r                                                                    98  2-methyl-4,6-hepta-                                                                           B       2-[3-(2-methylhepta-                                  dien-3-ol Chem.         4,6-dienyl)amino-                                     Abst. 71, 112534z       phenylacetic acid                                 99  E-2,4,6-trimethyl-                                                                            B       2-[E-2(2,4,6-hepta-                                   3,5-heptadien-2-ol      3,5-dienyl)amino]-                                                            benzoic acid                                     100  4,6-octadien-3-ol                                                                             B       3-(1-hexa-2,4-di-                                     Chem. Abst. 69,         enylamino)phenyl-                                     58770s                  acetic acid                                      101  2,4-hexadien-1-ol                                                                             B       2-(1-hexa-2,4-di-                                     Chem. Abst. 67,         enylamino)benzoic                                     81787s                  acid                                             102  6-isopropyl-7,7-                                                                              B       3-[2-6-isopropyl-7,                                   dimethyl-3,5-octa-      7-dimethylocta-3,5-                                   dien-2-ol Chem.         dienyl)amino] phenyl-                                 Abst. 75, 36362g        acetic acid                                      103  3,5,7-trimethyl-                                                                              B       2-[3-(3,5,7-tri-                                      4,6-nonadien-3-ol       methylnona-4,                                         Chem. Abst. 74,         6-dienyl)amino]-                                                              benzoic acid                                     104  2,6-dimethyl-3,5-                                                                             B       3-[2-(2,6-dimethyl-                                   octadien-2-ol           octa-3,5-dienyl)-                                     Chem. Abst. 68,         amino]phenylacetic                                    114750d                 acid                                             105  E,E-6-ethyl-4,6-                                                                              B       2-[E,E-3-(6-ethyl-                                    decadien-3-ol Chem.     deca-4,6-dienyl)-                                     Abst. 73, 130585n       amino]benzoic acid                               106  5-ethyl-3,5-nona-                                                                             B       3-[2-(5-ethylnona-                                    dien-2-ol               3,5-dienyl)amino]-                                                            phenylacetic acid                                107  E,E-2,4-octadien-                                                                             B       2-(E,E-1-octa-2-                                      1-ol Chem. Abst.        4-dienylamino)-                                       67, 104946n             benzoic acid                                     108  E,Z-2,4-nonadien-                                                                             B       3-(E,Z-1-nona-2-                                      1-ol Chem. Abst.        4-dienylamino)-                                       67, 99692w              phenylacetic acid                                109  E,E-2,4-decadien-                                                                             B       2-(E,E-1-deca-2-                                      1-ol Chem. Abst.        4-dienylamino)-                                       67, 104946n             benzoic acid                                     110  E,Z-2,4-decadien-                                                                             B       3-E,Z-1-deca-2-                                       1-ol Chem. Abst.        4-dienylamino)-                                       67, 99692v              phenylacetic acid                                111  E-2,5-hexadien-1-ol                                                                           B       2-(E-1-hexa-2,5-dienyl-                               Chem. Abst. 73,         amino)phenylacetic                                    P55709a                 acid                                             112  Z-2,5-hexadienyl-                                                                             B       3-(Z-1-hexa-2,5-dienyl-                               1-ol Chem. Abst.        amino)benzoic acid                                    73, PS5709a                                                              113  E(+)-4-ethyl-2,5-di-                                                                          B       2-(E(+)-1-(2,5-dimeth-                                methyl-2,5-hexadien-    ylhexa-2,5-dienyl)-                                   1-ol Chem. Abst.        amino]phenylacetic                                    71, 70152m              acid                                             114  E-2,5,5-trimethyl-                                                                            B       3-[ E-2-(2,5,5-trimeth-                               3,6-heptadien-1-ol      ylhepta-3,6-dienyl-                                   Chem. Abst. 74,         amino]benzoic acid                                    52962n                                                                   115  Z-2,5,5-trimethyl-                                                                            B       2-[Z-2-(2,5,5-trimeth-                                3,6-heptadien-1-        ylhepta-3,6-dienyl)-                                  ol Chem. Abst 74,       amino]phenylacetic                                    52962n                  acid                                             116  Z,E-3,7-dimethyl-                                                                             B       3-[Z-E-1-(3,7-dimethyl-                               2,5-octadien-1-ol       octa-2,5-dienyl)amino[-                               Chem. Abst. 71,         benzoic acid                                          6156a                                                                    117  E-2,6-dimethyl-2,6-                                                                           B       2-[E-1-(2,6-dimethyl-                                 heptadien-1-ol          hept-2,6-dienyl)amino]                                Chem. Abst. 72,         phenylacetic acid                                     32036u                                                                   118  E,E-2,6-octadien-                                                                             B       3-(E,E-1-octa-2,6-dien-                               1-ol                    ylamino)benzoic acid                             119  E,E-2,6-dimethyl-                                                                             B       2-[E,E-1-(2,6-dimethyl-                               2,6-octadien-           octa-2,6-dienyl)amino]-                               1-ol Chem. Abst.        phenylacetic acid                                     71, 22204n                                                               120  Z,E-2,6-dimethyl-                                                                             B       3-(Z,E-1-(2,6-dimethyl-                               octadien-1-ol           octa-2,6-dienylamino)-                                Chem. Abst.             benzoic acid                                          71, 22204n                                                               121  E,Z-2,6-nonadien-                                                                             B       2-(E,Z-1-nona-2,6-di-                                 1-ol Chem. Abst.        enylamino)phenylacetic                                72, 245043              acid                                             122  E,Z-3,ethyl-7-  B       2-[E,Z-1-(3-ethyl-7-                                  methyl-2,6-nonadien-    methylnona-2,6-dienyl)-                               1-ol Chem. Abst.        amino]benzoic acid                                    75, 63019g                                                               123  3,7,11,11-tetrameth-                                                                          B       3-[1-(3,7,11,11-tetra-                                yl-2,6-dodecadien-      methyldodeca-2,6-di-                                  1-ol Chem. Abst. 75,    enyl)amino]phenyl-                                    P117969n                acetic acid                                      124  E,E-3,7,11-trimeth-                                                                           B       2-[E,E-1-(3,7,11-tri-                                 yl-2,6-dodecadien-      methyldodeca-2,6-di-                                  1-ol Chem. Abst.        enyl)amino]benzoic                                    69, 978z                acid                                             125  E-Z-3,7,11-trimethyl-                                                                         B       3-(E,Z-1-(3,7,11-tri-                                 2,6-dodecadien-1-ol     methyldodeca-2,6-di-                                  Chem. Abst.             enyl)amino]phenyl-                                    69, 978g                acetic acid                                      126  2,7-octadien-1-ol                                                                             B       2-(1-octa-2,7-dienyl-                                 Chem. Abst. 74,         amino)benzoic acid                                    P41892p                                                                  127  E-3,7-dimethyl-2,7-                                                                           B       3-[E-1-(3,7-di-                                       octadien-1-ol           methylocta-2,7-di-                                    Chem. Abst. 68,         enyl)amino]phenyl-                                    114750d                 acetic acid                                      128  Z,3,7-dimethyl- B       2-[Z-1-(3,7-di-                                       2,7-octadien-1-ol       methylocta-2,7-di-                                    Chem. Abst. 68,         enyl)amino]benzoic                                    114750d                 acid                                             129  3,4,8-trimethyl-                                                                              B       3-[1-(3,4,8-tri-                                      2,7-nonadien-1-ol       methylnona-2,7-di-                                    Chem. Abst. 68,         enyl)amino]phenyl-                                    9184c                   acetic acid                                      130  3,4,8-trimethyl-                                                                              B       2-[1-(3,4,8-tri-                                      2,8-nonadien-           methylnona-2,8-di-                                    1-ol Chem. Abst.        enyl)amino]benzoic                                    68, 29184c              acid                                             131  2,9-decadien-1-ol                                                                             B       3-(1-deca-2,9-di-                                     Chem. Abst.             enylamino)phenyl-                                     68, 68373h              acetic acid                                      132  E,3,7,11-trimethyl-                                                                           B       2-[E-1-(3,7,11-tri-                                   2,10dodecadien-1-ol     methyldodeca-2,10-                                    Chem. Abst.             dienylamino]phenyl-                                   69, 978z                acetic acid                                      133  Z-3,7,11-trimethyl-                                                                           B       3-[Z-1-(3,7,11-tri                                    2,10-dodecadien-1-ol    methyldodeca-2,10-                                                            dienyl)amino]-                                                                benzoic acid                                     134  E,E-4-methyl-3,5-                                                                             B       2-[E,E-1-(4-methyl-                                   heptadien-1-ol          hepta-3,5-dienyl)-                                    Chem. Abst.             amino]phenylacetic                                    66, 104730s             acid                                             135  E,Z-4-methyl-3,5-                                                                             B       3-[E,Z-1-(4-methyl-                                   heptadien-1-ol          hepta-3,5-dienyl)-                                    Chem. Abst.             amino]benzoic acid                                    66, 104730s                                                              136  Z-E-4-methyl-3,5-                                                                             B       2-[Z,E-1-(4-methyl-                                   heptadien-1-ol          hepta-3,5-dienyl)                                     Chem. Abst.             amino]phenylacetic                                    66, 104730s             acid                                             137  Z,Z-4-methyl-3,5-                                                                             B       3-[Z,Z-1-(4-methyl-                                   heptadien-1-ol          hepta-3,5-dienyl)-                                    Chem. Abst. 66,         amino]benzoic acid                                    104730s                                                                  138  E-4,6-dimethyl-3,5-                                                                           B       2-[E-1-(4,6-di-                                       heptadien-1-ol          methylhepta-3,                                        Chem. Abst. 66,         5-dienyl)amino]-                                      104730s                 phenylacetic acid                                139  Z-4,6-dimethyl-3,5-                                                                           B       3-[Z-1-(4,6-di-                                       heptadien-1-ol          methylhepta-3,                                        Chem. Abst. 66,         5-dienylamino]-                                       104730s                 benzoic acid                                     140  E,Z-2,6-dimethyl-4,6-                                                                         B       2-[E,Z-2-(2,6-di-                                     octadien-2-ol Chem.     methylocta-4,6-di-                                    Abst. 68, 114750d       enyl)amino]phenyl-                                                            acetic acid                                      141  1-hydroxy-3,7,11-                                                                             B       3-[1-(3,7,11-tri-                                     trimethyl-2,6,10-       methyldodeca-2,6,                                     dodecatriene            10-trienyl)amino]-                                                            benzoic acid                                     142  5-methyl-3,5-octa-                                                                            B       2-[1-(5-methylocta-                                   dien-1-ol               3,5-dienyl)amino]-                                    Chem. Abst.             benzoic acid                                          69, 18519k                                                               143  E-4-methyl-3,6- B       3-[E-1-(4-methyl-                                     heptadien-1-ol          hepta-3,6-dienyl)-                                    Chem. Abst.             amino]phenylacetic                                    66, 104730s             acid                                             144  Z-4-methyl-3,6- B       2-[Z-1-(4-methyl-                                     heptadien-1-ol          hepta-3,6-dienyl)-                                    Chem. Abst.             amino]benzoic acid                                    66, 104730s                                                              145  E(+)-2,6-dimethyl-                                                                            B       3-[E(+)-2-(2,6-di-                                    4,7-octadien-2-ol       methylocta-4,7-di                                     Chem. Abst. 75,         enyl)amino]phenyl-                                    49345d                  acetic acid                                      146  Z(+)-2,6-dimethyl-                                                                            B       2-[Z(+)-2-(2,6-di-                                    4,7-octadien-2-ol       methylocta-4,7-di-                                    Chem. Abst. 75,         enyl)benzoic acid                                     49345d                                                                   147  E-3,7-dimethyl-3,6-                                                                           B       3-[E-1-(3,7-di-                                       octadien-1-ol           methylocta-3,6-di-                                    Chem. Abst.             enyl)amino]phenyl-                                    67, 64554z              acetic acid                                      148  E-3,7 dimethyl-3,6-                                                                           B       2-[Z-1-(3,7-di-                                       octadien-1-ol           methylocta-3,6-di-                                                            enyl)amino]benzoic                                                            acid                                             149  Z-3-methyl-3,7- B       3-[E-1-(3-methyl-                                     octadien-1-ol           octa-3,7-dienyl)-                                     Chem. Abst. 69,         amino]phenylacetic                                    65681x                  acid                                             150  Z-3-methyl-3,7- B       2-[Z-1-(3-methyl-                                     octadien-1-ol           octa-3,7-dienyl)-                                     Chem. Abst. 69,         amino]benzoic acid                                    26681x                                                                   151  E-2-methyl-4,8-nona-                                                                          B       3-[Z-1-(4,6-di-                                       dien-1-ol               methylhepta-3,5-di-                                   Chem. Abst. 73,         enyl)amino]phenyl-                                    87253p                  acetic acid                                      152  E-3,7-dimethyl-3,7-                                                                           B       2-[E-1-(3,7-di-                                       octadien-1-ol Chem.     methylocta-3,7-di-                                    Abst. 69, 26681x        enylamino]phenyl-                                                             acetic acid                                      153  E-8-methyl-7-   B       3-[E-1-(8-methyl-7-                                   methylene-3-nonen-      methylenenon-3-enyl)-                                 1-ol Chem. Abst.        amino]benzoic acid                                    70, 29098u                                                               154  2,4,9-trimethyl-                                                                              B       2-[2-(2,4,9-tri                                       4,8-decadien-1-ol       methyldeca-4,8-di-                                    Chem. Abst.             enyl)amino]phenyl-                                    74, 99342s              acetic acid                                      155  E-2-methyl-4,9- B       3-[E-2-(2-methyldeca-                                 decadien-1-ol           4,9-dienyl)amino]-                                    Chem. Abst.             benzoic acid                                          73, 87254g                                                               156  2,6-dimethyl-5,7                                                                              B       2-[2-(2,6-dimethyl-                                   octadien-2-ol           octa-5,7-dienyl)-                                     Chem. Abst.             amino]phenylacetic                                    72, 37616t              acid                                             157  E-3,7-dimethyl- B       3-[E-1-(3,7-dimeth-                                   4,6-octadien-1-ol       ylocta-4,6-dienyl)-                                   Chem. Abst. 72,         amino]benzoic acid                                    121291r                                                                  158  Z-3,7-dimethyl- B       2-[Z-1-(3,7-dimeth-                                   4,6-octadien-1-ol       ylocta-4,6-dienyl)-                                   Chem. Abst. 72,         amino]phenylacetic                                    121291r                 acid                                             159  E-4,7-octadien-1-ol                                                                           B       3-[E-1-(octa-4,7-di-                                  Chem. Abst.             enyl)amino]benzoic                                    66, 28610k              acid                                             160  5,8-nonadien-2-ol                                                                             B       2-[2-(nona-5,8-di-                                    Chem. Abst. 68          enyl)amino]phenyl-                                    28610k                  acetic acid                                      161  E-7-methyl-4,7- B       3-[E-1-(7-methyl-                                     octadien-1-ol           octa-4,7-dienyl)-                                     Chem. Abst. 66,         amino]benzoic acid                                    28619k                                                                   162  E-8-methyl-5,8- B       2-[E-2-(8 methyl-                                     nonadien-2-ol           nona-5,8-dienyl)-                                     Chem. Abst. 66,         amino]benzoic acid                                    28610k                                                                   163  E-6,10-dimethyl-                                                                              B       3-[E-2-(6,10 di-                                      5,9-undecadien-         methylundeca-5,9-di-                                  2-ol Chem. Abst.        enyl)amino]phenyl-                                    73, 1331152f            acetic acid                                      164  5,9,13-trimethyl-                                                                             B       2-[6-(5,9,13-tri-                                     8,13-tetradecadien-     methyltetradeca-8,                                    2-ol Chem. Abst.        12-dienyl)amino]-                                     70, 28303v              benzoic acid                                     165  E-3,7,11-trimethyl                                                                            B       3-[E-3-(3,7,11-tri-                                   6,10-dodecadien-        methyldodeca-6,                                       3-ol Chem. Abst.        10-dienyl)amino]-                                     69, 8333f               phenylacetic acid                                166  z-3,7,11-trimethyl-                                                                           B       2-[Z-3-(3,7,11-tri-                                   6,10-dodecadien-        methyldodeca-6,                                       3-ol Chem. Abst.        10-dienyl)amino]-                                     69, 8333f               benzoic acid                                     167  5,9-dimethyl-4,8-                                                                             B       3-[1-(5,9-dimethyl-                                   decadien-1-ol           deca-4,8-dienyl)-                                     Chem. Abst.             amino]phenylacetic                                    74, 112233n             acid                                             168  15-methanesulfonyl-                                                                           B       2-[1-pentadeca-4,14-                                  oxy-1,11-pentadeca-     dienylamino)benzoic                                   diene Ref. B            acid                                             169  5,7-octadien-1-ol                                                                             B       3-[1-octa-5,7-dienyl-                                 Chem. Abst.             amino)phenylacetic                                    68, 688503a             acid                                             170  E-3,7-dimethyl- B       2-[E-1(3,7-dimeth-                                    5,7-octadien-           octa-5,7-dienyl)-                                     1-ol Chem. Abst.        amino]benzoic acid                                    72, P90672j                                                              171  6,10-dimethyl-  B       3-[1-(6,10-dimethyl-                                  5,9-undecadien-         undeca-5,9-dienyl)-                                   1-ol Chem. Abst.        amino]phenylacetic                                    71, 50248y              acid                                             172  2,6,10-trimethyl--                                                                            B       2-[1-(2,6,10-tri-                                     5,9-undecadien-         methylundeca-5,9-di-                                  1-ol Chem. Abst.        enyl)amino]phenyl-                                    71, 50243t              acetic acid                                      173  10-propyl-5,9-tri-                                                                            B       3-[1-(10-propyl-                                      decadien-1-ol           trideca-5,9-dienyl)-                                  Chem. Abst.             amino]benzoic acid                                    68, 39028u                                                               174  5,13-tetradecadien-                                                                           B       2-[1-tetradeca-5,13-                                  2-ol Chem. Abst.        dienylamino]phenyl-                                   66, 35672k              acetic acid                                      175  E-3,7,11-trimethyl-                                                                           B       3-[1-(3,7,11-tri-                                     6,10-dedecadien-        methyldodeca-6, -                                     1-ol Chem. Abst.        10-dienyl)amino]-                                     69, 978z                benzoic acid                                     176  E-6,10,14-trimethyl-                                                                          B       2-[E-2-(6,10,14-tri-                                  9,13-pendadecadien-     methylylpentadeca-                                    2-ol Chem. Abst.        9,13-dienyl)amino]-                                   74, 53992j              phenylacetic acid                                177  Z-6,10,14-trimethyl-                                                                          B       3-8 Z-2-(6,10,14-tri-                                 9,13-pentadecadien-     methylylpentadeca-                                    2-ol Chem. Abst.        9,13-dienyl)amino]-                                   74, 53992j              benzoic acid                                     178  Z,Z-9,12-octadecadien-                                                                        B       2-(1-octadeca-9,12-                                   2-ol Chem. Abst.        dienylamino)phenyl-                                   68, 92804V              acetic acid                                      179  E,Z-10,12-hexadeca-                                                                           B       3-[E,Z-1-hexadeca-                                    dien-1-ol Chem. Abst.   10,12-dienylamino)-                                   66 106133y              benzoic acid                                     180  Z,E-10,12-hexadeca-                                                                           B       2-[Z,E-1-hexadeca-                                    dien-1-ol Chem. Abst.   10,12-dienylamino)-                                   66, P7956f              phenylacetic acid                                181  2-methyl-2,3-buta-                                                                            B       3-[1-(2-methylbuta-                                   dien-1-ol               2,3-dienyl)amino]-                                    Chem. Abst.             benzoic acid                                          71, 30229n                                                               182  2-ethyl-2,3-buta-                                                                             B       2-[1-(2-ethylbuta-                                    2,4-hexadien-2-ol       2,3-dienyl)amino]-                                    Chem. Abst.             phenylacetic acid                                     67, 535673e                                                              183  2,3,5-trimethyl-                                                                              B       2-[2-(2,3,5-tri-                                      3,4-hexadien-2-ol       methylhexa-3,4-di-                                    Chem. Abst.             enyl)amino]benzoic                                    72, 131953x             acid                                             184  3-isopropyl-2,4-di-                                                                           B       3-[3-(2,4-dimethyl-                                   methyl-4,5-hexadien-    hexa-4,5-dienyl)-                                     3-ol                    amino]phenylacetic                                                            acid                                             185  2,5-dimethyl-3,4-                                                                             B       2-[2-(2,5-dimethyl-                                   hexadien-2-ol           hexa-3,4-dienyl)-                                     Chem. Abst.             amino]benzoic acid                                    68, 39152e                                                               186  3,5-dimethyl-3,4-                                                                             B       3-[2-(3,5-dimethyl-                                   heptadien-2-ol          hepta-3,4-dienyl)-                                    Chem Abst.              amino]phenylacetic                                    72, 131953x             acid                                             187  2-methyl-3,4-   B       2-[2-(2-methylhepta-                                  heptadien-2-ol          3,4-dienyl)amino]-                                    Chem. Abst.             benzoic acid                                          71, 38219g                                                               188  2,3,5-trimetyl- B       3-[2-(2,3,5-tri-                                      3,4-heptadien-2-ol      methylhepta-3,4-di-                                   Chem. Abst.             enyl)amino]phenylacetic                               72, 131953x             acid                                             189  3-t-butyl-2-meth-                                                                             B       2-[2-(3-t-butyl-                                      yl-3,4-octadien-        2-methylocta-3,4-di-                                  2-ol Chem. Abst.        entyl)amino]benzoic                                   66, 75593s              acid                                             190  2-ethyl-2,3-    B       3-[1-(2-ethylhepta-                                   heptadien-1-ol          2,3-dienyl)amino]-                                    Chem. Abst.             phenylacetic acid                                     75, 63063s                                                               191  2-methyl-3,4-   B       2-[1-(2-methylocta-                                   octadien-2-ol           3,4-dienyl)amino]-                                    Chem. Abst.             benozic acid                                          75, 140175g                                                              192  3-methyl-3,4-   B       3-[2-3-(3-methyl-                                     octadien-2-ol           octa-3,4-dienyl)-                                     Chem. Abst.             amino]phenylacetic                                    66, 75593s              acid                                             193  5,6-decadien-4-ol                                                                             B       2-(4-deca-5,6-di-                                     Chem. Abst.             enylamino)phenyl-                                     75, 76898t              acetic acid                                      194  2,3-dimethyl-3,4-                                                                             B       3-[2-(2,3-dimethyl-                                   octadien-2-ol           octa-3,4-dienyl)-                                     Chem. Abst.             amino]benzoic acid                                    66, 75593s                                                               195  4-ethyl-4,5-    B       2-[3-(4-ethylnona-                                    nonadien-3-ol           4,5-dienyl)amino]-                                    Chem. Abst.             phenylacetic acid                                     75, 63063s                                                               196  2-methyl-3-propyl-                                                                            B       3-[2-(2-methyl-                                       3,4-octadien-2-ol       3-propylocta-3,4-di-                                  Chem. Abst.             enyl)amino]benzoic                                    66, 65592v              acid                                             197  2-methyl-3,4-   B       2-[2-(2-methylnona-                                   nonadien-2-ol           3,4-dienyl)amino]-                                    Chem. Abst.             phenylacetic acid                                     75, 140173g                                                              198  2,8-dimethyl-3,4-                                                                             B       3-[2-(2,8-dimethyl-                                   nonadien-2-ol           nona-3,4-dienyl)-                                     Chem. Abst.             amino]benzoic acid                                    71, 38219g                                                               199  2-methyl-3,4-deca-                                                                            B       2-]2-(2-methyldeca-                                   dien-2-ol Chem.         3,4-dienyl)amino]-                                    Abst. 75, 140173g       phenylacetic acid                                200  2,9-dimethyl-3,4-                                                                             B       3-[2-(2,9-dimethyl-                                   decadien-2-ol           deca-3,4-dienyl)-                                                             amino]benzoic acid                               201  2-methyl-3,4-dodeca-                                                                          B       2-[2-(2-methyldo-                                     dien-2-ol Chem.         deca-3,4-dienyl)-                                     Abst. 71, 38219g        amino]phenylacetic                                                            acid                                             202  2-methyl-3,4-tri-                                                                             B       3-[2-(2-methyltri-                                    decadien-1-ol Chem.     deca-3,4-dienlyl)-                                    Abst. 71, 38219g        amino]benzoic acid                               203  4,5-hexadien-2-ol                                                                             B       2-(2-hexa-4,5-di-                                     Chem. Abst.             enylamino)benzoic                                     75, 5152j               acid                                             204  2-methyl-5,6-   B       3-[2-(2-methylhepta-                                  heptadien-3-ol          5,6-dienyl)amino]-                                    Chem. Abst.             phenylacetic acid                                     75, 5152j                                                                205  3,3-dimethyl-4,5-                                                                             B       2-[2-(3,3-dimethyl-                                   hexadien-2-ol           hexa-4,5-dienyl)-                                     Chem. Abst.             amino]benzoic acid                                    69, 86256x                                                               206  2,5-dimethyl-5,6-                                                                             B       3-[2-(2,5,dimethyl-                                   heptadien-3-ol          hepta-5,6-dienyl)-                                    Chem. Abst.             amino]phenylacetic                                    68, 86855w              acid                                             207  2,2,5-trimethyl-                                                                              B       2-[1-(2,2,5-tri-                                      3,4-hexadien-1-ol       methylhexa-3,4-di-                                    Chem. Abst.             enyl)amino] benzoic                                   71, 29767g              acid                                             208  (+) 2,2-dimethyl-                                                                             B       3-[1-(2,2-dimethyl-                                   3,4-hexadien-1-ol       hexa-3,4-dienyl)-                                     Chem. Abst.             amino]phenylacetic                                    68, 58831s              acid                                             209  3,4-hexadien-1-ol                                                                             B       2-[1-hexa-3,4-di-                                     Chem. Abst.             enylamino)benzoic                                     66, 54943r              acid                                             210  2,2,3,5-tetramethyl-                                                                          B       3-[1-(2,2,3,5-tetra-                                  3,4-hexadien-1-ol       methylhexa-3,4-di-                                    Chem. Abst.             enyl)amino]phenyl-                                    71, 29767g              acetic acid                                      211  3,3,6-trimethyl-                                                                              B       2-[2-(3,3,6-trimeth-                                  4,5-octadien-2-ol       ylocta-4,5-dienyl)-                                   Chem. Abst. 69,         amino]benzoic acid                                    86256x                                                                   212  2,5-dimethyl-5,6-                                                                             B       3-[2-(2,5-dimethyl-                                   heptadien-2-ol Chem.    hepta-5,6-dienyl)-                                    Abst. 69, 86256x        amino]phenylacetic                                                            acid                                             213  4-methyl-4-penten-                                                                            B       2-[1-(4-methylpent-                                   2-yn-1-ol               4-en-2-ynyl)amino]-                                                           phenylacetic acid                                214  2-methyl-2-penten                                                                             B       3-[1-(2-methylpent-                                   2-yn-1-ol               2-en-4-ynyl)amino]-                                                           benzoic acid                                     215  5-hexen-3-yn-2-ol                                                                             B       2-[2-hex-5-en-3-                                                              ynylamino)phenyl-                                                             acetic acid                                      216  7-octen-5-yn-4-ol                                                                             B       3-[4-oct-7-en-5-ynyl-                                 Chem. Abst. 67,         amino)benzoic acid                                    113544g                                                                  217  5-methyl-5-hexen-                                                                             B       2-[2-(5-methylhex-                                    3-yn-2-ol               5-en-3-ynyl)amino]-                                                           phenylacetic acid                                218  2,5-dimethyl-1-nonen-                                                                         B       3-[5-(2,5-dimethyl-                                   3-yn-5-ol Chem.         non-1-en-3-ynyl)-                                     Abst. 69, 2433s         amino]benzoic acid                               219  E-3-decen-1-yn-5-ol                                                                           B       2-(5-dec-3-en-1-ynyl-                                 Chem. Abst. 75,         amino]phenylacetic                                    35042r                  acid                                             220  E-3-dodecen-1-yn-5-ol                                                                         B       3-(5-dodec-3-en-                                      Chem. Abst. 75, 35042r  1-ynylamino)benzoic                                                           acid                                             221  2-methyl-5-hexen-3-                                                                           B       2-[2-(2-methylhex-5-                                  yn-2-ol Chem. Abst.     en-3-ynyl)amino]-                                     66, 75760v              phenylacetic acid                                222  3-methyl-6-hepten-4-                                                                          B       3-[3-(3-methylhept-                                   yn-3-ol Chem. Abst.     6-en-4-ynyl)amino]-                                   67, 113544g             benzoic acid                                     223  5-methyl-1-nonen-3-                                                                           B       2-[5-(5-methylnon-1-                                  yn-5-ol Chem. Abst.     en-3-ynyl)amino]-                                     67, 43345s              phenylacetic acid                                224  3-ethyl-6-hepten-4-                                                                           B       3-[3-(3-ethylhept-                                    yn-3-ol Chem. Abst.     6-en-4-ynyl)amino]-                                   71, 112202g             benzoic acid                                     225  5-ethyl-1-nonen-3-                                                                            B       2-[5-(5-ethylnon-1-                                   yn-5-ol Chem. Abst.     en-3-ynyl)amino]-                                     72, 31124j              benzoic acid                                     226  2,5-dimethyl-5-hexen-                                                                         B       3-[2-(2,5-dimethyl-                                   3-yn-2-ol Chem. Abst.   hex-5-en-3-ynyl)-                                     71, 112202g             amino]phenylacetic                                                            acid                                             227  3,6-dimethyl-6-hepten-                                                                        B       2-[2-(2,5-dimethyl-                                   4-yn-3-ol Chem. Abst.   hex-5-en-3-ynyl)-                                     69, 96881m              amino]benzoic acid                               228  3-ethyl-6-methyl-                                                                             B       3-[3-(3-ethyl-                                        6-hepten-4-yn-3-ol      6-methylhept-6-en-                                    Chem. Abst. 71,         4-ynylamino]phenyl-                                   1122026                 acetic acid                                      229  5-ethyl-2-methyl-                                                                             B       2-[5-(5-ethyl-                                        3-yn-5-ol Chem. Abst.   2-methyl-n-1-en-                                      69, 2433s               3-ynyl)amino]benzoic                                                          acid                                             230  2-hexen-4-yn-1-ol                                                                             B       3-(1-(hex-2-en-                                       Chem. Abst.             4-ynylamino)phenyl-                                   68, 77868a              acetic acid                                      231  4-methyl-4-hexen-2-                                                                           B       2-[1-(4-methylhex-4-                                  yn-1-ol Chem. Abst.     en-2-ynyl)amino]-                                     66, 11524r              benzoic acid                                     232  5-hexen-2-yn-1-ol                                                                             B       3-(1-hex-5-en-2-ynyl-                                 Chem. Abst. 71,         amino)phenylacetic                                    80580t                  acid                                             233  5-methyl-5-hexen-2-                                                                           B       2-[1-(5-methylhex-                                    yn-1-ol Chem. Abst.     5-en-2-ynyl)amino]-                                   70, 28152v              benzoic acid                                     234  5-hexen-3-yn-1-ol                                                                             B       3-(1-hex-5-en-                                        Chem. Abst. 73,         3-ynylamino)phenyl-                                   109833g                 acetic acid                                      235  E-4-methyl-5-yn-1-ol                                                                          B       2-[E-1-(4-methyl-                                     Chem. Abst. 66,         hept-3-en-5-ynyl)-                                    104730s                 amino]benzoic acid                               236  z-4-methyl-5-yn-1-ol                                                                          D       .2-[z-1-(4-methyl-                                    Chem. Abst. 66,         hept-3-en-5-ynyl)-                                    104730s                 amino]phenylacetic                                                            acid                                             237  3-hexen-5-yn-2-ol                                                                             B       3-(2-hex-3-en-                                        Chem. Abst. 75,         5-ynylamino)benzoic                                   5152j                   acid                                             238  6-methyl-6-hepten-                                                                            B       2-[2-(6-methylhept-                                   4-yn-2-ol               6-en-4-ynyl)amino]-                                                           phenylacetic acid                                239  7-methyl-7-octen-                                                                             B       3-[3-(7-methyloct-                                    5-yn-3-ol               7-en-5-ynyl)amino]-                                                           benzoic acid                                     240  2,5-dimethyl-5-hex-                                                                           B       2-[2-(2-dimethylhex-                                  en-3-yn-2-ol            5-en-3-ynyl)amino]-                                                           phenylacetic acid                                241  3-methyl-6-octen-                                                                             B       3-[3-(3-methyloct-                                    4-yn-3-ol Chem.         6-en-4-ynyl)amino]-                                   Abst. 74, 41795j        benzoic acid                                     242  5-methyl-9-decen-                                                                             B       2-[5-(5-methyldec-                                    6-yn-5-ol Chem.         9-en-6-ynyl)amino] -                                  Abst. 73, 125271c       phenylacetic acid                                243  2,5,5,6-tetrameth-                                                                            B       3-[2-(2,5,5,6-tetra-                                  yl-6-hepten-3-yn-       methylhept-6-en-3-                                    2-ol Chem. Abst.        ynyl)amino]-                                          70, 10801w              benzoic acid                                     244  3-ethyl-7-octen-                                                                              B       2-[3-(3-ethyloct-                                     4-yn-3-ol Chem.         7-en-4-ynyl)amino]-                                   Abst. 73, 3762t         phenylacetic acid                                245  3-methyl-7-octen-                                                                             B       3-[3-(3-methyloct-                                    4-yn-3-ol Chem.         7-en-4-ynyl)amino]-                                   Abst. 73, 3762t         benzoic acid                                     246  2,6-dimethyl-6- B       2-[2-(2,6-dimethyl-                                   hepten-3-yn-2-ol        hept-6-en-3-ynyl)-                                    Chem. Abst. 73,         amino]phenylacetic                                    55677p                  acid                                             247  3,6-diethyl-6-  B       3-[3-(3,6-diethyl-                                    octen-4-yn-3-ol         oct-6-en-4-ynyl)-                                     Chem. Abst. 68,         amino]benzoic acid                                    104850x                                                                  248  6-ethyl-6-octen-                                                                              B       2-[2-(6-ethyloct-                                     4-yn-2-ol Chem.         6-en-4-ynyl)amino]-                                   Abst. 73, 19632z        benzoic acid                                     249  6-methyl-6-hepten-                                                                            B       3-[1-6-methylhept-                                    2-yn-1-ol Chem.         6-en-2-ynyl)amino]-                                   Abst. 72, 3587u         phenylacetic acid                                250  E-4-methyl-3-hept-                                                                            B       2-[E-1-(4-methyl-                                     en-6-yn-1-ol Chem.      hept-3-en-4-ynyl)-                                    Abst. 66, 104730s       amino]benzoic acid                               251  z-4-methyl-3-hept-                                                                            B       3-[z-1-(4-methyl-                                     en-5-yn-1-ol Chem.      hept-3-en-6-ynyl)-                                                            acid                                             252  E-2-octen-6-yn- B       2-(E-1-oct-2-en-6-                                    1-ol Chem. Abst.        ynylamino)-                                           75, 63019g              benzoic acid                                     253  z-7-methyl-6-non-                                                                             B       3-[z-1-(7-methyl-                                     en-2-yn-1-ol Chem.      non-6-en-2-ynyl)-                                     Abst. 70, 78718j        amino]phenylacetic                                                            acid                                             254  8-methyl-7-methyl-                                                                            B       2-[1-(8-methyl-1-                                     ene-3-nonyn-1-ol        methylenenon-                                         Chem. Abst. 66,         3-ynyl)amino]benzoic                                  29098u                  acid                                             255  E-2-decen-4-yn- B       3-(1-dec-2-en-                                        1-ol Chem. Abst.        4-ynylamino)phenyl-                                   67, 99692v              acetic acid                                      256  4-methyl-4-decen-                                                                             B       2-[1-(4-methyldec-                                    8-yn-1-ol Chem.         4-en-8-ynyl)amino]-                                   Abst. 75, 110510x       benzoic acid                                     257  E-2-undecen-4-yn-                                                                             B       3-(1-undec-2-en-                                      1-ol Chem. Abst.        4-ynylamino)phenyl-                                   66, 28594h              acetic acid                                      258  6-methyl-5-undecen-                                                                           B       2-[1-(6-methylundec-                                  2-yn-1-ol Chem.         5-en-2-ynyl)amino]-                                   Abst. 71, p101399h      benzoic acid                                     259  E-5-tetradecen-3-                                                                             B       3-(E-1-tetradec-                                      yn-1-ol Chem.           5-en-3-ynylamino)-                                    Abst. 73, 87370z        phenylacetic acid                                260  z-5-tetradecen-3-                                                                             B       2-(z-1-tetradec-                                      yn-1-ol Chem.           5-en-3-ynylamino)-                                    Abst. 73, 87370z        phenylacetic acid                                261  10-propyl-9-tridec-                                                                           B       3-[1-(10-propyltri-                                   en-5-yn-1-ol            dec-9-en-5-ynyl)-                                     Chem. Abst. 72,         amino]benzoic acid                                    12017k                                                                   262  17-octadecen-14-yn-                                                                           B       2-(1-octadec-17-en-                                   1-ol Chem. Abst.        14-ynylamino)phenyl-                                  68, 39015n              acetic acid                                      263  2,4-dimethyl-1,4-                                                                             B       3-[3-(2,4-dimethyl-                                   hexadien-3-ol           hexa-1,4-dienyl)-                                     Chem. Abst. 74,         amino]benzoic acid                                    87269u                                                                   264  1,5-hexadien-3-ol                                                                             B       2-(3-hexa-1,5-di-                                     Chem. Abst. 73,         enylamino)phenyl-                                     44822f                  acetic acid                                      265  3,5-dimethyl-1,5-                                                                             B       3-[3-(3,5-dimethyl-                                   hexadien-3-ol           hexa-1,5-dienyl)-                                     Chem. Abst. 67,         amino]benzoic acid                                    53415d                                                                   266  2,6-dimethyl-1,6-                                                                             B       2-[3-(2,6-dimethyl-                                   heptadien-3-ol          hepta-1,6-dienyl)-                                    Chem. Abst. 73,         amino]phenylacetic                                    87490p                  acid                                             267  E-2,6-dimethyl-1,6-                                                                           B       3-[E-3-(2,6-di-                                       octadien-3-ol Chem.     methylocta-1,6-di-                                    Abst. 71, 61565a        enyl)amino]benzoic                                                            acid                                             268  z-2,6-dimethyl-1,6-                                                                           B       2-[z-3-(2,6-di-                                       octadien-3-ol Chem.     methylocta-1,6-di-                                    Abst. 71, 61565a        enyl)amino]phenyl-                                                            acetic acid                                      269  3-ethyl-7-methyl-                                                                             B       3-[3-(3-ethyl-                                        1,6-octadien-3-ol       7-methylocta-1,6-di-                                  Chem. Abst. 66,         enyl)amino]benzoic                                    p76192x                 acid                                             270  3-t-butyl-7-methyl-                                                                           B       2-[3-(3-1-butyl-                                      1,6-octadien-3-ol       7-methylocta-1,6-di-                                  Chem. Abst. 66,         enyl9amino]phenyl-                                    p76192x                 acetic acid                                      271  7,9-dimethyl-1,6-                                                                             B       2-[3-(7,9-dimethyl-                                   decadien-3-ol           deca-1,6-dienyl)-                                     Chem. Abst. 71,         amino]benzoic acid                                    p60078c                                                                  272  3,7-dimethyl-1,6-                                                                             B       3-[3-(3,7-dimethyl-                                   decadien-3-ol           deca-1,6-dienyl)-                                     Chem. Abst. 67,         amino]phenylacetic                                    2688n                   acid                                             273  2-methyl-1,5-   B       2-[4-(2-methylhepta-                                  heptadien-4-ol          1,5-dienyl)amino]-                                    Chem. Abst. 67,         benzoic acid                                          53415d                                                                   274  4,6-dimethyl-1,5-                                                                             B       3-[4-(4,6-dimethyl-                                   heptadien-4-ol          hepta-1,5-dienyl)-                                    Chem. Abst. 67,         amino]phenylacetic                                    53415d                  acid                                             275  E,E-3,4,5-trimethyl-                                                                          B       2-[E,E-4-(3,4,5-tri-                                  2,5-heptadien-4-ol      methylhepta-2,5-di-                                   Chem. Abst. 72,         enyl)amino]benzoic                                    2823f                   acid                                             276  E,Z-3,4,5-trimethyl-                                                                          B       3-[E,Z-4-(3,4,5-tri-                                  2,5-heptadien-4-ol      methylhepta-2,5-di-                                   Chem. Abst. 72,         enyl)amino]phenyl-                                    2823f                   acetic acid                                      277  z,z-3,4,5-trimethyl-                                                                          B       2-[z,z-4-(3,4,5-tri-                                  2,5-heptadien-4-ol      methylhepta-2,5-di-                                   Chem. Abst. 72,         enyl)amino]benzoic                                    2823f                   acid                                             278  2-methyl-2,9-   B       3-[5-(2-methyldeca-                                   decadien-5-ol           2,9-dienyl)amino]-                                    Chem. Abst. 73,         phenylacetic acid                                     87254q                                                                   279  8-methyl-1,7-nona-                                                                            B       2-[5-(8-methylnona-                                   dien-5-ol Chem.         1,7-dienyl)amino]-                                    Abst. 73, 87253p        benzoic acid                                     280  3,4,7,7-tetrameth-                                                                            B       3-[5-(3,4,7,7-tetra-                                  yl-1,5-octadien-4-      methylocta-1,5-dienyl)-                               ol Chem. Abst. 67,      enyl)amino]phenyl-                                    63514z                  acetic acid                                      281  3,4-dimethylene-2-                                                                            B       2-[2-(3,4-dimethylene-                                hexanol Chem. Abst.     hexyl)amino]benzoic                                   69, 106850s             acid                                             282  3-methyl-2-methyl-                                                                            B       2-[1-(3-methyl-                                       ene-3-butene-1-ol       2-methylenebut-                                       Chem. Abst. 74,         3-enyl)amino]phenyl-                                  42503z                  acetic acid                                      283  2-methylene-3-  B       3-[1-(2-methylene-                                    buten-1-ol Chem.        but-3-enyl)amino]-                                    Abst. 73, p67478n       benzoic acid                                     284  3,3-dimethyl-2- B       2-[1-(3,3-demethyl-                                   methylene-4-penten-     2-methylenepent-                                      1-ol Chem. Abst.        4-enyl)amino]phenyl-                                  74, 52962n              acetic acid                                      285  2-methylene-3-meth-                                                                           B       3-[1-(2-methylene-                                    yl-4-hexen-1-ol         3-methylhex-4-enyl)-                                  Chem. Abst. 68          amino]benzoic acid                                    59021q                                                                   286  2,4-dimethyl-3- B       2-[2-(2,4-dimethyl-                                   methylene-5-hexen-      3-methylenehex-                                       2-ol Chem. Abst.        5-enyl)amino]-                                        72, 66299x              phenylacetic acid                                287  2,4,4-trimethyl-3-                                                                            B       3-[2-(2,4,4-tri-                                      methylene-5-hexen-      methyl-3-methylene-                                   2-ol Chem. Abst.        hex-5-enyl)amino]-                                    74 ,52962n              benzoic acid                                     288  E-2-methyl-3-methyl-                                                                          B       2 [E-2-(2-methyl-                                     ene-5-hepten-2-ol       3-methylenehept-                                      Chem. Abst. 72,         5-enyl)amino]phenyl-                                  132999d                 acetic acid                                      289  z-2-methyl-3-methyl-                                                                          B       3-[z-2-(2-methyl-3-                                   ene-5-hepten-2-ol       methylenehept-5-                                      Chem. Abst. 72,         enyl)amino]benzoic                                    132999d                 acid                                             290  2-dimethyl-1,3- B       2-[2-(2,6-dimethyl-                                   methylene-5-hepten-     3-methylenehept-5-                                    2-ol Chem. Abst.        enyl)amino]phenyl-                                    72, 132999d             acetic acid                                      291  3,7-dimethyl-2- B       3-[1-(3,7-dimethyl-                                   methylene-6-octen-      2-methyleneoct-                                       1-ol Chem. Abst.        6-enyl)amino]-                                        68, 1114750d            benzoic acid                                     292  3,7-dimethyl-2- B       2-[1-(3,7-dimethyl-                                   methylene-7-octen-      2-methyleneoct-                                       1-ol Chem. Abst.        7-enyl)amino]-                                        70, p37191j             benzoic acid                                     293  3-isopropylidene-                                                                             B       3-[2-(3-isopropyl-                                    2,5-dimethyl-4-hex-     idene-2,5-dimethyl-                                   en-2-ol Chem. Abst.     hex-4-enyl)amino]-                                    74, 53105x              phenylacetic acid                                294  2-methyl-6-methyl-                                                                            B       2-[4-(2-methyl-                                       ene-7-octen-4-ol        6-methyleneoct-                                       Chem. Abst. 69,         7-enyl)amino]benzoic                                  10548y                  acid                                             295  2-isopropylidene-                                                                             B       3-[1-(2-isopropyl-                                    5-methyl-4-hexene-      idene-5-methylhex-                                    1-ol Chem. Abst.        4-enyl)amino]phenyl-                                  72, 132999d             acetic acid                                      296  7-methyl-3-methyl-                                                                            B       2-[1-(7-methyl-                                       ene-6-octen-1-ol        3-methyleneoct-                                       Chem. Abst. 73,         6-enyl)amino]-                                        131140a                 benzoic acid                                     297  2-methyl-6-methyl-                                                                            B       3-[2-(2-methyl-                                       ene-7-octen-2-ol        6-methyleneoct-                                       Chem. Abst. 71,         6-enyl)amino]-                                        p61600h                 phenylacetic acid                                298  E-2-ethylidene-6-                                                                             B       2-[E-1-(2-ethyl-                                      methyl-5-hepten-1-ol    idene-6-methylhept-                                   Chem. Abst. 68,         5-enyl)amino]benzoic                                  114750d                 acid                                             299  z-2-ethylidene-6-                                                                             B       3-[z-1-(2-ethyl-                                      methyl-5-hepten-1-ol    idene-6-methylhept-                                   Chem. Abst. 68,         5-enyl)amino]phenyl-                                  114750d                 acetic acid                                      300  2,5-dimethyl-3- B       2-[2-(2,5-dimethyl-                                   vinyl-4-hexen-2-ol      3-vinylhex-4-enyl)-                                   Chem. Abst. 69,         amino]benzoic acid                                    45983p                                                                   301  2-isopropenyl-5-                                                                              B       3-[1-(2-isopropenyl-                                  methyl-4-hexen-1-ol     5-methylhex-4-enyl)-                                  Chem. Abst. 68,         amino]phenylacetic                                    111190k                 acid                                             302  2-vinyl-5-hepten-                                                                             B       2-[1-(2-vinylhept-                                    1-ol Chem. Abst.        5-enyl)amino]phenyl-                                  75, p151673w            acetic acid                                      303  2-vinyl-6-hepten-                                                                             B       3-[1-(2-vinylhept-                                    1-ol Chem. Abst.        6-enyl)amino]benzoic                                  75, p15167w             acid                                             304  2-(2-methylpropen-                                                                            B       2-[1-(2-methylpro-                                    yl)-5-hexen-1-ol        penylhex-5-enyl)-                                     Chem. Abst. 68,         amino]phenylacetic                                    114750d                 acid                                             305  7-methyl-3-vinyl-                                                                             B       3-[1-(7-methyl-                                       6-octen-1-ol Chem.      3-vinyloct-6-enyl)-                                   Abst. 66, p115838j      amino]benzoic acid                               306  2-allyl-4-methyl-4-                                                                           B       2-[1-2-allyl-                                         penten-1-ol Chem.       4-methylpent-                                         Abst. 72, 21731r        4-enyl)amino]phenyl-                                                          acetic acid                                      307  3-methyl-5-undecen-                                                                           B       3-[3-(3-methylundec-                                  1-yn-3-ol Chem.         5-en-1-ynyl)amino]-                                   Abst. 71, p101399h      benzoic acid                                     308  3,4,8-trimethyl-8-                                                                            B       2-[3-(3,4,8-tri-                                      nonen-1-yn-3-ol         methylnon-8-en-                                       Chem. Abst. 68,         1-ynylamino]phenyl-                                   29184r                  acetic acid                                      309  1-dodecen-4-yn-3-ol                                                                           B       3-(3-dodec-1-en-                                      Chem. Abst. 66,         4-ynylamino)benzoic                                   75603v                  acid                                             310  11-dedecen-1-yn-3-ol                                                                          B       2-(3-dodec-11-en-                                     Chem. Abst. 73,         1-ynylamino)phenyl-                                   120015n                 acetic acid                                      311  1-undecen-5-yn-4-ol                                                                           B       3-(4-undec-1-en-                                      Chem. Abst. 69,         5-ynylamino)benzoic                                   2432r                   acid                                             312  3,7-dimethyl-6- B       2-[3-(3,7-dimethyl-                                   nonen-1-yn-3-ol         non-6-en-1-ynyl)-                                     Chem. Abst. 71,         amino]phenylacetic                                    p91265v                 acid                                             313  7,7-dimethyl-1-non-                                                                           B       2-[5-(7,7-dimethyl-                                   en-8-yn-5-ol Chem.      non-1-en-8-ynyl)-                                     Abst. 74, 22939t        amino]benzoic acid                               314  2,3-dimethyl-1-non-                                                                           B       3-[3-(2,5-kimethyl-                                   en-4-yn-3-ol Chem.      non-1-en-4-ynyl)-                                     Abst. 68, 39161g        amino]phenylacetic                                                            acid                                             315  3,7-dimethyl-7- B       2-[3-(3,7-dimethyl-                                   octen-1-yn-3-ol Chem.   oct-7-en-1-ynyl)-                                     Abst. 73, p7095a        amino]benzoic acid                               316  4,6-dimethyl-5-hept-                                                                          B       3-[3-(4,6-kimethyl-                                   en-1-yn-4-ol Chem.      hept-5-en-1-ynyl)-                                    Abst. 66, 95156e        amino]phenylacetic                                                            acid                                             317  1-penten-4-yn-3-ol                                                                            B       2-(3-pent-1-en-                                       Chem. Abst. 74,         4-ynylamino)benzoic                                   p140935m                acid                                             ______________________________________                                    

PREPARATION OF ESTERS

Treatment of the acids of Examples 1-317 and 321-358 with trifluoraceticanhydride to provide the N-COCF₃ derivative, followed by treatment withthionyl chloride to provide the N-COCF₃ acid chloride, followed bytreatment with one of the following alcohols, followed by removal of theN-COCF₃ group with 1 N sodium hydroxide solution at 20° C. provides thecorresponding ester of the starting acid.

Alcohols: methanol, ethanol, 2-methoxyethanol, butanol, pentanol,cyclopentanol, cyclohexanol, 1,2-propanediol, 1,3-propanediol, ethyleneglycol, glycerol, glycidol, methyl glycolate, ethyl glycolate, glycolicacid, 2-hydroxypropionic acid, 3-hydroxybutyric acid, 4-hydroxybutyricacid, glyceric acid, 3-diethylamino-1-propanol,1-diethylamino-2-propanol, 3-dimethylamino-1-propanol,2-diisopropylaminoethanol, 3-(4-methyl-1-piperazino)-1,2-propanediol,3-methoxy-1,2-propanediol, N-piperidineethanol, N,N-diethylethanolamine.

EXAMPLE 319 Preparation of 2-[1-(2,3-methano)octylamino]phenylaceticacid

To a stirred mixture of 5 g. of zinc-copper couple prepared by theShank-Shechter Method [R. S. Shank and H. Schehter, J. Org. Chem., 24,1825 (1959)], 0.02 g. of iodine, and 100 ml. of anhydrous ether is added8.7 g. of (0.05 mol) of methylene iodide. The mixture is heated in theabsence of atmospheric moisture until a spontaneous reaction begins asevidenced by continued refluxing of the ether when the heat source isremoved. Upon completion of the exothermic reaction, the mixture isrefluxed for 30 minutes, the heat is removed and to this mixture isadded a solution of 5.4 g. (0.04 mol) of cis-2-octenol [L. P. Paquetteand R. F. Eizember, J. Am. Chem. Soc., 91, 7110 (1969)] in 10 ml. ofanhydrous ether at a rate sufficient to maintain constant reflux. Whenthe addition is complete, the mixture is refluxed for 3 hours. The flaskis cooled and the mixture is filtered and the filtrate is washed withcold dilute hydrochloric acid and saturated sodium bicarbonate, driedand evaporated to give Z-1-hydroxymethyl-2-n-pentylcyclopropane.

Preparation of the tosylate by the method of Example 2, followed bycondensation with ethyl 2-aminophenylacetate by the method of Example 2,followed by saponification by the method of Example 2 provides2-[1-(2,3-methano)octylamino]phenylacetic acid.

EXAMPLE 320

Treatment of the indicated olefin of the Table II with zinc anddiiodomethane by the method of Example 319 to produce the correspondingcyclopropyl compound followed by treatment of the halide with, forexample, ethyl 2- or 3-aminophenylacetate or methyl 2- or3-aminobenzoate by the method of Example 1, followed by saponificationof the resulting ester by the method of Example 1, is productive,respectively, of a 2- or 3-(methanoalkyl)aminophenylacetic acid or a 2-or 3-(methanoalkyl)aminobenzoic acid of Table II (Method C).

Treatment of the olefinic alcohols of Table II with zinc anddiiodomethane by the method of Example 319 will produce thecorresponding cyclopropyl alkanols which upon treatment withmethanesulfonic anhydride (Method of Example 2) will produce thecorresponding methanesulfonate ester which upon treatment with, forexample, ethyl 2- or 3-aminophenylacetate or methyl 2- or3-aminobenzoate by the procedure of Example 2 followed by saponificationwill produce the 2- or 3-(methanoalkyl)aminophenylacetic acids or the 2-or 3-(methanoalkyl)aminobenzoic acids of Table II (Methods D).

                  TABLE II                                                        ______________________________________                                        Exam-                                                                         ple   Starting Material                                                                            Method   Product                                         ______________________________________                                        321   3-bromo-3-isopropyl-                                                                         C        2-[3-(3-isopropyl-                                    4-methyl-1-pentene      4-methyl-1,2-methano-                                 Chem. Abst. 54,         pentyl)amino]phenyl-                                  4355a                   acetic acid                                     322   4-bromo-2-heptene                                                                            C        3-[4-(2,3-methano-                                    Chem. Abst. 70,         heptyl)amino]benzoic                                  67482x                  acid                                            323   4-bromo-2,4-dimeth-                                                                          C        2-[4-(2,4-dimethyl-                                   yl-2-hexene Chem.       2,3-methanohexyl)-                                    Abst. 70, 3169t         amino]phenylacetic                                                            acid                                            324   5-chloro-3,5-dimeth-                                                                         C        3-[5-(3,5-dimethyl-                                   yl-3-heptene Chem.      3,4-methanoheptyl)-                                   Abst. 54, 1256e         amino]benzoic acid                              325   z-1-hydroxy-2-hexa-                                                                          D        2-[z-1-(2,3-methano-                                  decene Ref. B           hexadecyl)amino]-                                                             phenylacetic acid                               326   E-1-hydroxy-2-hexa-                                                                          D        2-[E-1-(2,3-methano-                                  decene Ref. B           hexadecyl)amino]-                                                             benzoic acid                                    327   1-bromo-4-methyl-3-                                                                          C        3-[1-(4-methyl-3,-                                    heptene Chem. Abst.     4-methanoheptyl)-                                     71, 102020q             amino]phenylacetic                                                            acid                                            328   1-bromo-4-methyl-3-                                                                          C        2-[1-(4-methyl-3,4-                                   heptene Chem. Abst.     methanononyl)amino]-                                  71, P101399h            benzoic acid                                    329   E-7-bromo-3-heptene                                                                          C        3-[E-1-(4,5-methano-                                  Chem. Abst. 74,         heptyl)amino]phenyl-                                  99419 f                 acetic acid                                     330   1-bromo-5,9-dimeth-                                                                          C        2-[1-(5,9-dimethyl-                                   yl-4-decene Chem.       4,5-methanodecyl)-                                    Abst. 51, 8699g         amino benzoic acid                              331   1-methanesulfonyloxy-                                                                        C        3-[1-(4,5-methano-                                    4-tetradecene Ref. B    tetradecyl)amino]-                                                            phenylacetic acid                               332   1-methanesulfonyloxy-                                                                        C        2-[1-(4,5-methano-                                    4-hexadecene Ref. B     hexadecyl)amino]-                                                             benzoic acid                                    333   6-bromo-1-hexene                                                                             C        3-[1-(5,6-methano-                                    Chem. Abst 66,          hexyl)amino]phenyl-                                   2142j                   acetic acid                                     334   6-bromo-2-methyl-                                                                            C        2-[1-(5,6-methano-                                    1-hexene Chem.          5-methylhexyl)amino]-                                 Abst. 75, 109624f       benzoic acid                                    335   6-chloro-1-heptene                                                                           C        3-[2-(6,7-methano-                                    Chem. Abst. 72,         heptyl)amino]phenyl-                                  31877g                  acetic acid                                     336   6-bromo-2-methyl-2-                                                                          C        2-[2-(5,6-methano-                                    heptene Chem. Abst.     6-methylheptyl)-                                      54, 13166f              amino]benzoic acid                              337   7-chloro-2-octene                                                                            C        3-[2-(6,7,-methano-                                   Chem. Abst. 75          octyl)amino]phenyl-                                   129245m                 acetic acid                                     338   E-1-chloro-4-nonene                                                                          C        2-[E-1-(4,5-methano-                                  Chem. Abst. 67,         nonyl)amino]phenyl-                                   32294y                  acetic acid                                     339   7-bromo-1-heptene                                                                            C        3-[1-(6,7-methano-                                                            heptyl)amino]benzoic                                                          acid                                            340   7-chloro-1-octene                                                                            C        2-[2-(7,8-methano-                                    Chem. Abst, 75,         octyl)amino]phenyl-                                   129245m                 acetic acid                                     341   6-bromo-6-methyl-                                                                            C        3-[1-(2-methyl-6,7-                                   1-heptene Chem.         methanoheptyl)amino]-                                 Abst. 66, 94482w        benzoic acid                                    342   6-chloro-2-methyl-                                                                           C        2-[1-(6-methyl-6,7-                                   1-heptene Chem.         methanoheptyl)amino]-                                 Abst. 75, 129245        phenylacetic acid                               343   E-8-bromo-2-octene                                                                           C        3-[1-(6,7-methano-                                    Chem. Abst. 74,         octyl)benzoic acid                                    99419f                                                                  344   8-bromo-2,6-dimeth-                                                                          C        2-[1-(3,7-dimethyl-                                   yl-2-octene Chem.       6,7-methanooctyl)-                                    Abst. 72, 90573c        amino]phenylacetic                                                            acid                                            345   11-bromo-5-undecene                                                                          C        3-[1-(6,7-methanoun-                                  Chem. Abst. 67,         decyl)amino]benzoic                                   73101b                  acid                                            346   8-bromo-1-octene                                                                             C        2-[1-(7,8-methano-                                    Chem. Abst. 70,         octyl)amino]phenyl-                                   10990g                  acetic acid                                     347   R-8-iodo-7-methyl-                                                                           C        3-[1-(2-methyl-7,8-                                   1-octene Chem.          methanooctyl)amino]-                                  Abst. 74, 12573e        benzoic acid                                    348   1-chloro-7-tetra-                                                                            C        2-[1-(7,8-methano-                                    decene Chem. Abst.      tetradecyl) amino]-                                   54, 22461h              phenylacetic acid                               349   9-chloro-1-nonene                                                                            C        3-[1-(8,9-methano-                                    Chem. Abst. 70,         nonyl)amino]benzoic                                   114490k                 acid                                            350   1-bromo-8-hepta-                                                                             C        2-[1-(8,9-methano-                                    decene Chem. Abst.      heptadecyl)amino]-                                    52, 249d                benzoic acid                                    351   E-1-bromo-9-octa-                                                                            C        3-[E-1-(9,10-methano-                                 decene Chem. Abst.      octadecyl)amino]-                                     70, 47799j              phenylacetic acid                               352   z-1-bromo-9-octa-                                                                            C        2-[z-1-(9,10-methano-                                 decene Chem. Abst.      octadecyl)amino]-                                     70, 46779j              benzoic acid                                    353   11-chloro-1-undec-                                                                           C        3-[1-(10,11-methano-                                  ene Chem. Abst.         undecyl)amino]-                                       66, P19046d             phenylacetic acid                               354   12-iodo-3,7,11-tri-                                                                          C        2-[1-(2,6,10-tri-                                     methyl-1-dodecene       methyl-11,12-                                                                 methanododecyl)-                                                              amino]benzoic acid                              355   13-bromo-1-tri-                                                                              C        3-[1-(12,13-methano-                                  decene Chem. Abst.      tridecyl)amino]-                                      67, 43348v              phenylacetic acid                               356   22-bromo-9-docos-                                                                            C        2-[1-(13,14-methano-                                  ene Chem. Abst.         docosyl)amino]-                                       73, 44976j              benzoic acid                                    357   16-methanesulfonyl-                                                                          C        3-[1-(15,16-methano-                                  oxy-1-hexadecene        hexadecyl)amino]-                                     Ref. B                  phenylacetic acid                               358   3-chloro-2,4,4-tri-                                                                          C        1-[3-(2,4,4-tri-                                      methyl-1-pentene        methyl]-1,2-methano-                                  Chem. Abst. 72,         pentyl)amino]benzoic                                  1110811                 acid                                            ______________________________________                                    

EXAMPLE 359 2,3-Dihydroxypropyl 2-(4-pentadecenyl)aminophenyl]acetate

A solution of 7.35 g. of 2-(4-pentadecenyl)aminophenylacetic acid in 50ml. of hexamethylphosphoramide is treated with 4.80 g. of 25% aqueoussodium hydroxide followed by 11.0 g. of 3-chloro-1,2-propanediol andthen is heated at 140° C. for 6 hours. The mixture is diluted with waterand ether and filtered to yield a white solid. Recrystallization fromacetonitrile and then from carbon tetrachloride affords the product as awhite solid.

EXAMPLE 360 2,3-Dihydroxypropyl 3-(4-tetradecenylamino)phenylbutyrate

A mixture of 2.25 g. of methyl 3-(4-tetradecenylamino)phenylbutyrate,280 mg. of glycerol, and 1.37 g. of p-touluenesulfonic acid is heated at180° C. for 18 hours and then is partitioned between ether and 3%aqueous sodium carbonate solution. The ether layer is separated, dried,and evaporated to yield the product as a white solid.

EXAMPLE 361 2,3-Dihydroxypropyl 2-(4-tetradecenylamino)phenylpropionate

A solution of 11.8 g. of 2-(4-tetradecenylamino)phenylpropionic acid,1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200ml. of toluene is stirred under reflux for 48 hours. The solution istreated with an additional 5.35 ml. of boron trifluoride etherate andrefluxing is continued for 120 hours. Dilution with water and methylenechloride followed by filtration affords the product as a white solid.

EXAMPLE 362 Preparation of 3-(allylamino)hydrocinnamic acid

A 4 g. sample of ethyl 3-(allylamino)hydrocinnamate is hydrolyzed with1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing thesolution for 5 hours. The solution is cooled, diluted with 100 ml. waterand acidified to pH 4.5 with 37% hydrochloric acid. The precipitate iscollected, dried in vacuo and crystallized from acetone to yield thetitle compound as white powder.

EXAMPLE 363 Preparation of 1-methanesulfonyloxyoctadec-9-ene

To a mixture of 250 ml. of dichloromethane, 25 g. 1-hydroxyoctadec-9-eneand 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. isadded dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride.The mixture is cooled at -10° C. to -15° C. for 30 minutes and thenwashed with 300 ml. each of cold water, 10% hydrochloric acid, sodiumcarbonate solution and with saturated sodium chloride solution. Theorganic layer is dried with magnesium sulfate and concentrated in vacuoto give a pale yellow oil.

EXAMPLE 364 Preparation of ethyl 2-(1-pentadec-4-enylamino)phenylacetate

To a cold (-20°) stirred solution of 10.8 g. 1-hydroxypentadec-4-eneprepared by lithium aluminum hydride reduction of methyltetradec-3-encarboxylate and 13.4 ml. triethylamine in 300 ml. ether isadded dropwise 5.6 ml. methanesulfonyl chloride in 5 ml. of either.After addition is completed, the solution is warmed to room temperature,stirred for 30 minutes and filtered directly into a solution of 23.1 g.ethyl 2-aminophenyl acetate in 100 ml. ether. After 17 hours at roomtemperature, the precipitate is filtered and washed with severalportions of methylene chloride. The organic solution is washed twicewith 100 ml. water, 100 ml. brine, dried and evaporated. The tan residueis crystallized from ethanol and from acetonitrile to yield the titlecompound as white crystals.

EXAMPLE 365 Preparation of ethyl3-(1-pentadeca-4,14-dienylamino)hydrocinnamate

A solution of 8.6 ethyl 3-aminohydrocinnamate, 9.77 g.3,13-tetradecadien-1-carboxaldehyde and a few crystals of2,4-dinitrobenzenesulfonic acid in 250 ml. toluene is refluxed under aDean-Stark trap for 17 hours, whereupon the theoretical amount (0.8 ml.)water has been collected. The toluene is evaporated to yield ethyl3-[3-(1-pentadeca-4,14-dienylideneaminophenyl]propionate as acrystalline mass.

To a mixture of 17.8 g. of the above compound in 250 ml. ethanol isadded 1.68 g. sodium borohydride and the mixture is stirred at roomtemperature for 18 hours. Excess reagent is decomposed by addition of 10ml. acetic acid. The solution is concentrated in vacuo and the residueis partitioned between toluene and aqueous potassium carbonate. Afterdrying, the toluene is evaporated to yield a solid. Crystallization fromacetonitrile and from ethanol affords the title compound as whitecrystals.

EXAMPLE 366 Preparation of ethyl3-[2-(3,7,11-trimethyldodeca-2,6,10-trienylamino)phenyl]propionate

A mixture of 5.0 g. of ethyl 2-aminohydrocinnamate, 10.0 g. of1-methanesulfonyloxy-3,7,11-triemethyldodeca-2,6,10-triene (prepared bythe method of Example 363), 4.2 g. of anhydrous powdered potassiumcarbonate and 40 ml. hexamethylphosphoramide is heated to 80° C. for 17hours. The mixture is then cooled, diluted with water and extracted withethyl ether. The ether extracts are washed with water, dried andevaporated. The residue is recrystallized from ethanol yielding thetitle compound as white crystals.

EXAMPLE 367 Preparation of ethyl2-[1-(6-decylhept-6-enyl)amino]cinnamate

A mixture of ethyl 2-aminocinnamate, 5.9 g. 6-decylhept-6-enylbromideand one equivalent of anhydrous powdered potassium carbonate in 50 ml.hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture isthen cooled, diluted with water and extracted with ether. The combinedether extracts are dried, filtered and evaporated. Crystallization fromacetonitrile provides the title compound as white crystals.

TABLE III

The following 2- or 3-(substituted-amino)hydrocinnamates are preparedfrom the appropriate starting material by the method shown. Alcohols areconverted to the corresponding mesylates by the method of Example 363.

    ______________________________________                                        Example                                                                              Method of                                                              No.    Example   2- or 3-(Substituted-amino)hydrocinnamate                    ______________________________________                                        368    364       Ethyl 2-(allylamino)hydrocinnamate                           369    367       Ethyl 3-(1-octadec-9-enylamino)hydro-                                         cinnamate                                                    370    365       Ethyl 2-(1-pentadec-4-enylamino)-                                             hydrocinnamate                                               371    366       Ethyl 3-(1-tetradec-4-enylamino)hydro-                                        cinnamate                                                    372    367       Ethyl 2-(1-pentadec-4,14-dienylamino)-                                        hydrocinnamate                                               373    364       Ethyl 3-[1-(3,7,11-trimethyldodeca-2,6,-                                      10-trienyl)amino]hydrocinnamate                              374    366       Ethyl 2-[1-(6-decylhept-6-enyl)amino]-                                        hydrocinnamate                                               375    364       Ethyl 3-[4-(2,3-methanoheptyl)amino]-                                         hydrocinnamate                                               ______________________________________                                    

TABLE IV

The following 2- or 3-(substituted-amino)hydrocinnamic acids areprepared from the esters of Table III by the method of Example 362.

    ______________________________________                                        Example                                                                       No.     2- or 3-(Substituted-amino)hydrocinnamic acid                         ______________________________________                                        376     2-(Allylamino)hydrocinnamic acid                                      377     3-(1-Octadec-9-enylamino)hydrocinnamic acid                           378     2-(1-Pentadec-4-enylamino)hydrocinnamic acid                          379     3-(1-Tetradec-4-enylamino)hydrocinnamic acid                          380     2-(1-Pentadec-4,14-dienylamino)hydrocinnamic acid                     381     3-[1-(3,7,11-Trimethyldodeca-2,6,10-trienyl)-                                 amino]hydrocinnamic acid                                              382     2-[1-(6-Decylhept-6-enyl)amino]hydrocinnamic acid                     383     3-[4-(2,3-Methanoheptyl)amino]hydrocinnamic acid                      ______________________________________                                    

TABLE V

The following 2- or 3-(substituted-amino)cinnamates are prepared fromthe appropriate starting materials by the methods shown. Alcohols areconverted to their corresponding mesylates by the method of Example 363.

    ______________________________________                                        Example                                                                              Method of                                                              No.    Example   2- or 3-(Substituted-amino)cinnamate                         ______________________________________                                        384    364       Ethyl 2-(allylamino)cinnamate                                385    367       Ethyl 3-(1-octadec-9-enylamino)cinnamate                     386    365       Ethyl 2-(1-pentadec-4-enylamino)-                                             cinnamate                                                    387    366       Ethyl 3-(1-tetradec-4-enylamino)-                                             cinnamate                                                    388    367       Ethyl 2-(1-pentadec-4,14-dienylamino)-                                        cinnamate                                                    389    364       Ethyl 3-[1-(3,7,11-trimethyldodica-2,6,-                                      10-trienyl)amino]cinnamate                                   390    366       Ethyl 2-[1-(6-decylhept-6-enyl)amino]-                                        cinnamate                                                    391    364       Ethyl 3-[4-(2,3-methanoheptyl)amino]-                                         cinnamate                                                    ______________________________________                                    

TABLE VI

The following 2- or 3-(substituted-amino)cinnamic acids are preparedfrom the esters of Table V by the method of Example 362.

    ______________________________________                                        Example                                                                       No.       2- or 3-(Substituted-amino)cinnamic acid                            ______________________________________                                        392       2-(Allylamino)cinnamic acid                                         393       3-(1-Octadec-9-enylamino)cinnamic acid                              394       2-(1-Pentadec-4-enylamino)cinnamic acid                             395       3-(1-Tetradec-4-enylamino)cinnamic acid                             396       2-(1-Pentadec-4,14-dienylamino)cinnamic acid                        397       3-[1-(3,7,1-Trimethyldodeca-2,6,10-trienyl                                    amino]cinnamic acid                                                 398       2-[1-(6-Decylhept-6-enyl)amino]cinnamic acid                        399       2-[4-(2,3-Methanoheptyl)amino]cinnamic acid                         ______________________________________                                    

TABLE VII

The following 2- or 3-(substituted-amino)phenylpropiolates are preparedfrom the appropriate starting materials by the methods shown. Alcoholsare converted to their corresponding mesylates by the method of Example363.

    ______________________________________                                        Example                                                                              Method of 2- or 3-(Substituted-amino)phenylpro-                        No.    Example   piolate esters                                               ______________________________________                                        400    365       Ethyl 2-(allylamino)phenylpropiolate                         401    367       Ethyl 3-(1-octadec-9-enylamino)phenyl-                                        propiolate                                                   402    367       Ethyl 2-(1-pentadec-4-enylamino)phenyl-                                       propiolate                                                   403    366       Ethyl 3-(1-tetradec-4-enylamino)-                                             phenylpropiolate                                             404    366       Ethyl 2-(1-pentadeca-4,14-dienylamino)-                                       phenylpropiolate                                             405    364       Ethyl 3-[1-(3,7,11-trimethyldodeca-2,6,-                                      10-trienyl)amino]phenylpropiolate                            406    364       Ethyl 2-[1-(6-decylhept-6-enyl)amino]-                                        phenylpropiolate                                             407    365       Ethyl 3-[4-(2,3-methanoheptyl)amino]-                                         phenylpropiolate                                             ______________________________________                                    

TABLE VIII

The following 2- or 3-(substituted-amino)phenylpropiolic acids areprepared from the esters of Table VII by the method of Example 362.

    ______________________________________                                        Example                                                                       No.      2- or 3-(Substituted-amino)phenypropiolic acid                       ______________________________________                                        408      2-(Allylamino)phenylpropiolic acid                                   409      3-(1-Octadec-9-enylamino)phenylpropiolic acid                        410      2-(1-Pentadec-4-enylamino)phenylpropiolic acid                       411      3-(1-Tetradec-4-enylamino)phenylpropiolic acid                       412      2-(1-Pentadeca-4,14-dienylamino)phenylpropiolic                               acid                                                                 413      3-[1-(3,7,11-Trimethyldodeca-2,6,10-trienyl)-                                 amino]phenylpropiolic acid                                           414      2-[1-(6-Decylhept-6-enyl)amino]phenylpropiolic                                acid                                                                 415      3-[4-(2,3-Methanoheptyl)amino]phenylpropiolic                                 acid                                                                 ______________________________________                                    

TABLE IX

The following 2- or 3-(substituted-amino)phenylbutyrates are preparedfrom the appropriate mesylates by the method of Example 366. Therequisite mesylates are prepared by the method of Example 363.

    ______________________________________                                        Example    2- or 3-(Substituted-amino)phenylbutyrate                          No.        esters                                                             ______________________________________                                        416        Ethyl 2-(allylamino)phenylbutyrate                                 417        Ethyl 3-(1-octadec-9-enylamino)phenyl-                                        butyrate                                                           418        Ethyl 2-(1-pentadec-4-enylamino)phenyl-                                       butyrate                                                           419        Ethyl 3-(1-tetradec-4-enylamino)phenyl                                        butyrate                                                           420        Ethyl 2-(1-pentadeca-4,14-dienylamino)-                                       phenylbutyrate                                                     421        Ethyl 3-[1-(3,7,11-trimethyldodeca-2,6,10-                                    trienyl)amino]phenylbutyrate                                       422        Ethyl 2-[1-(6-decylhept-6-enyl)amino]-                                        phenylbutyrate                                                     423        Ethyl 3-[4-(2,3-methanoheptyl)amino]-                                         phenylbutyrate                                                     ______________________________________                                    

TABLE X

The following 2- or 3-(substituted-amino)phenylbutyric acids areprepared from the esters of Table IX by the method of Example 362.

    ______________________________________                                        Example                                                                       No.      2- or 3-(Substituted-amino)phenybutyric acid                         ______________________________________                                        424      2-(Allylamino)phenylbutyric acid                                     425      3-(1-Octadec-9-enylamino)phenylbutyric acid                          426      2-(1-Pentadec-4-enylamino)phenylbutyric acid                         427      3-(1-Tetradec-4-enylamino)phenylbutyric acid                         428      2-(1-Pentadeca-4,14-dienylamino)phenylbutyric                                 acid                                                                 429      3-[1-(3,7,11-Trimethyldodeca-2,6,10-trienyl)-                                 amino]phenylbutyric acid                                             430      2-[1-(6-Decylhept-6-enyl)amino]phenylbutyric                                  acid                                                                 431      3-[4-(2,3-Methanoheptyl)amino]phenylbutyric acid                     ______________________________________                                    

EXAMPLE 432 Preparation of 2-[4-(2,3-methanoheptyl)amino]acetophenone

2-Aminoacetophenone is heated with 5 g.1-methanesulfonyloxy-2,3-methanoheptane (prepared by the method ofExample 363) in 50 ml. hexamethylphosphoramide containing anhydrouspotassium carbonate (1.9 g.) for 16 hours a 100° C. The solution iscooled to room temperature, filtered to remove solids, and the filtrateis diluted with cold water (50 ml.). The amber solid so obtained iscollected and washed with water. Recrystallization from ethanol followedby dichloromethane provides 2-[4-(2,3-methanoheptyl)amino]acetophenone.

TABLE XI

The following 2- or 3-(substituted-amino)acetophenones are prepared bythe method of Example 432. The requisite mesylates are prepared by themethod of Example 363.

    ______________________________________                                        Example                                                                       No.      2- or 3-(Substituted-amino)acetophenone                              ______________________________________                                        433      2-(Allylamino)acetophenone                                           434      3-(1-Octadec-9-enylamino)acetophenone                                435      2-(1-Pentadec-4-enylamino)acetophenone                               436      3-(1-Tetradec-4-enylamino)acetophenone                               437      3-(1-Pentadeca-4,14-dienylamino)acetophenone                         438      2-[1-(3,7,11-Trimethyldodeca-2,6,10-trienyl)-                                 amino]acetophenone                                                   439      3-[1-(6-Decylhept-6-enyl)amino]acetophenone                          440      2-[4-(2,3-Methanoheptyl)amino]acetophenone                           ______________________________________                                    

EXAMPLE 441 Preparation of sodium 3-(allylamino)phenylacetate

A mixture of 3.62 g. of 3-(allylamino)phenylacetic acid and 25 ml. ofethanol water (9:1) containing 0.400 g. of sodium hydroxide is stirredfor 4 hours. The mixture is filtered and the residue washed with 10 ml.of ethanol-water (9:1) and dried in vacuo for 24 hours to yield sodium3-(allylamino)phenylacetate as a white solid.

EXAMPLE 442 Preparation of 2-(1-octadec-9-enylamino)phenylacetylchloride

A cold solution of 25 g. 2-(1-octadec-9-enylamino)phenylacetic acid in500 ml. dimethoxyethane methylene chloride (4:1) is prepared and dryhydrochloric acid is bubbled through the solution until no moreprecipitate forms. The solution is treated with 25 ml. thionyl chlorideand refluxed until all of the precipitate has dissolved. The solventsare evaporated to yield the acid chloride hydrochloride as an orange,semi-crystalline mass.

EXAMPLE 443 Preparation of 2-(N-trifluoroacetyl-allylamino)phenylacetylchloride

A stirred ice-cold suspension of 9 g. 2-(allylamino)phenylacetic acid in100 ml. of dimethoxyethane and 16 ml. of pyridine is treated with 18 ml.of trifluoroacetic anhydride at 0° C. The solution is stirred for 30minutes at room temperature and then diluted with 300 ml. ether and 100g. ice. After stirring vigorously for 15 minutes, the phases areseparated, the ether solution is washed with brine, dried and evaporatedto a white, amorphous solid.

To a solution of 9.2 g. of the above solid in 30 ml. methylene chlorideand 0.5 ml. dimethylformamide is added 5.7 ml. thionyl chloride. After20 hours at reflux, the solvents are evaporated to yield2-(N-trifluoroacetylallylamino)phenylacetyl chloride as a light yellow,mobile oil.

EXAMPLE 444 Preparation of 3-(N-carbobenzyloxy-allylamino)phenylacetylchloride

To 15 g. 3-(allylamino)phenylacetic acid in 200 ml. warm chloroform isadded a solution of 12 g. sodium carbonate in 150 ml. water. To thevigorously stirred solution is added 10 g. carbobenzyloxy chloride.After 2 hours stirring at 40° C., the layers are separated, washed threetimes with 1 N hydrochloric acid, dried, and evaorated to an oil. Theoil is dissolved in 300 ml. toluene, treated with 15 ml. thionylchloride and the solution is refluxed for 5 hours. The solvents areevaporated and the residue is dissolved three times in toluene,evaporating each time ultimately to yield3-(N-carbobenzyloxy-allylamino)phenylacetyl chloride as a viscous,orange oil.

EXAMPLE 445 Preparation of1-[3-(N-tert-butyloxycarbonyl)-1-tetradec-4-enylamino]phenylacetylimidazole

A solution of 10 g. 3-(1-tetradec-4-enylamino)phenylacetic acid in 100ml. dioxane is treated with 4.0 g. tert-butylazidoformate and 10 ml.pyridine. After stirring at room temperature for 18 hours, the protectedamidoacid is precipitated from solution by the addition of 150 ml.water. The solid is collected, thoroughly dried, and dissolved in 200ml. of a mixture consisting of methylenechloride/dimethoxyethane/pyridine (1:4:1). This solution is stirredovernight at room temperature and the solvents are evaporated to yield1-[3-(N-tert-butyloxycarbonyl)-tetradec-4-enyl-amino]phenylacetylimidazole as an orange oil.

EXAMPLE 446 Preparation of diethyl2-[1-tetradec-4-enylamino)benzoylmalonate

A solution of 26.6 g. of diethyl malonate and 10 ml. of1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydridein 1,2-dimethoxyethane under argon. A solution of 17.3 g. of2-(1-tetradec-4-enylamino)benzoyl chloride hydrochloride in1,2-dimethoxyethane is then added. The reaction mixture is refluxed for4.5 hours, cooled, poured on ice, acidified, and extracted with ether.The ether solution is washed with water and saturated sodium chloridesolution, dried over anhydrous sodium sulfate and concentrated todryness. Addition of a small amount of ethanol to the residue gives asolid which is filtered and discarded. The ethanol filtrate isconcentrated and the residue is recrystallized from ether to yielddiethyl 2-(1-tetradec-4-enylamino)benzoylmalonate.

EXAMPLE 447 Preparation of tert-butyl ethyl3-(1-pentadeca-4,14-dienylamino)benzoylmalonate

A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydridein 1,2-dimethoxyethane under argon. A solution of 17.3 g. of3-(1-pentadeca-4,14-dienylamino)benzoyl chloride hydrochloride in1,2-dimethoxyethane is then added. The reaction mixture is refluxed for5 hours, cooled, poured on ice and extracted with ether. The ethersolution is washed with water and saturated sodium chloride solution,dried over anhydrous sodium sulfate and concentrated to dryness. Theresidue is then recrystallized from ether to yield tert-butyl ethyl4-(1-pentadeca-4,14-dienylamino)benzoylmalonate.

EXAMPLE 448 Preparation of ethyl 2-[3-(1-allylamino)benzoyl]acetoacetate

A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydridein 1,2-dimethoxyethane under argon. A solution of 17.3 g. of2-(1-allylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane isthen added. The reaction mixture is refluxed for 5 hours, cooled, pouredon ice and extracted with ether. The ether solution is washed with waterand saturated sodium chloride solution, dried over anhydrous sodiumsulfate and concentrated to dryness. Recrystallization from etheraffords ethyl 2-[2-(1-allylamino)benzoyl]acetoacetate as a white solid.

EXAMPLE 449 Preparation of ethyl3-(1-tetradec-4-enylamino)benzoylacetate

A solution of 3.0 g. of tert-butyl ethyl3-(1-tetradec-4-enylamino)benzoyl malonate 10 ml. of trifluoroaceticacid is warmed with stirring for 3 hours. The solution is poured ontoice and neutralized with potassium hydroxide. The resulting precipitateis collected by filtration, washed with water and dried.Recrystallization from chloroform affords ethyl3-(1-tetradec-4-enylamino)benzoylacetate.

EXAMPLE 450 Preparation of 2-(1-tetradec-4-enylamino)benzoylacetic acid

Two grams of ethyl 2-(1-tetradec-4-enylamino)benzoylacetate is added toa solution of potassium hydroxide in 50 ml. of 1:9 water-ethanol. Thereaction mixture is stirred for 24 hours at room temperature. Carefulneutralization with sulfuric acid gave a precipitate which is filtered,washed with water, and dried to yield2-(1-tetradec-4-enylamino)benzoylacetic acid.

EXAMPLE 451 Preparation of2'-(1-allylamino)-2-(methylsulfinyl)acetophenone

To a solution of 5.8 g. of dimethyl sulfoxide, dried over sieves, and 50ml. of tetrahydrofuran is slowly added 28 ml. of n-butyllithium (2.4 Min hexane). To this mixture is added 10 g. of methyl2-(1-allylamino)benzoate in 200 ml. of tetrahydrofuran. After two hours,the reaction mixture is poured onto ice, acidified with dilutehydrochloric acid and quickly extracted with chloroform. The chloroformextract is washed with water and saturated sodium chloride solution, anddried over anhydrous sodium sulfate. Concentration afford a solid whichis washed with 500 ml. of hot hexane, filtered while hot and then washedwith hexane. The white solid is dried in vacuo to yield2'-(1-allylamino)-2-(methylsulfinyl)acetophenone.

EXAMPLE 452 Preparation of3'-(1-allylamino)-2-(phenylsulfonyl)acetophenone

A solution of 864 mg. of sodium hydride and 5.3 g. ofmethylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 6° C.for one hour under an atmosphere of argon. To this solution is added asolution of 5.0 g. of methyl 3-(1-allylamino)benzoate in 50 ml. oftetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5hours. The mixture is cooled, poured onto ice, acidified with dilutehydrochloric acid to pH 3 and then extracted with chloroform. Theorganic layer is separated, washed with water and saturated sodiumchloride solution, dried over anhydrous sodium sulfate and thenconcentrated to dryness. The crude solid is chromatographed on silicagel, eluted with methylene chloride to yield3'-(1-allylamino)-2-(phenylsulfonyl)acetophenone.

EXAMPLE 453 Preparation of2'-(1-cyclopentylethylamino)-2-(phenylsulfinyl)acetophenone

To a solution of 6.2 g. of methylphenylsulfoxide, dried over sieves, and50 ml. of tetrahydrofuran is slowly added 28 ml. of n-butyllithium (2.4M in hexane). To this mixture is added 10 g. of a solution of methyl2-(1-allylamino)benzoate in 200 ml. of tetrahydrofuran. After two hours,the reaction mixture is poured onto ice, acidified with dilutedhydrochloric acid and quickly extracted with chloroform. The chloroformlayer is washed with water and saturated sodium chloride solution anddried over anhydrous sodium sulfate. Concentration affords a solid whichis washed with 500 ml. of hot hexane, filtered while hot, and thenwashed with 50 ml. of hexane. The white solid is dried in vacuo yielding2'-(1-allylamino)-2-(phenylsulfinyl)acetophenone.

EXAMPLE 454 Preparation of 3-[3'-(1-allylamino)benzoyl]-2,4-pentanedione

A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodiumhydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of28.7 g. of 3-(1-allylamino)benzoylchloride hydrochloride in1,2-dimethoxyethane is then added. The reaction mixture is stirred atroom temperature for 12 hours, cooled, poured onto ice and extractedwith ether. The ether solution is washed with water and saturated sodiumchloride solution dried over anhydrous sodium sulfate and concentrated.The residue is then chromatographed over silica gel to yield3-[3'-(1-allylamino)benzoyl]-2,4-pentanedione.

EXAMPLE 455 Preparation of methyl 3-[2-(1-allylamino)benzoyl]propionate

A mixture of 35 g. of 3-(2-acetamidobenzoyl)propionic acid, 700 ml. ofmethanol and 1.4 ml. of concentrated sulfuric acid is refluxed for 76hours. The solution is cooled to 35° C. and poured onto 7 g. ofanhydrous sodium acetate while stirring. The reaction mixture is stirredin an ice-bath. The solid is collected and washed with cold methanol toyield 3-(2-aminobenzoyl)propionate as a white solid. A mixture of thissolid, 9.2 g. of 1-allylbromide and 4.2 g of potassium carbonte isstirred for 20 hours at 125° C. under nitrogen. The mixture is thencooled to 25° C. and 30 ml. of water is added. After stirring, theproduct is filtered and washed with water. Recrystallization frommethanol affords methyl 3-[2-(1-allylamino)benzoyl]propionate as a whitesolid.

EXAMPLE 456 Preparation of 3-[3-(1-allylamino)benzoyl]propionic acid

A solution of 5.4 g. of methyl 3-[3-(1-allylamino)benzoyl]propionate isstirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml.of ethanol and 100 ml. of water, neutralized with hydrochloric acid. Thesolution is cooled to room temperature and filtered. The white solid iswashed with 50% aqueous ethanol and dried. The product is recrystallizedfrom ethanol to yield 3-[3-(1-allylamino)benzoyl]propionic acid.

TABLE XII

The following acetophenones are prepared by the noted methods from thecarboxylic acids of Tables I or II or appropriate derivatives thereofwhich are obtained by the methods of Examples 442-445.

    ______________________________________                                        Example                                                                              Method of 2- or 3-(Substituted-amino)aceto-                            No.    Example   phenones                                                     ______________________________________                                        457    446       Diethyl 2-[(1-tetradec-4-enyl)amino]-                                         benzoylmalonate                                              458    447       tert-Butyl ethyl 3-(1-allylamino)-                                            benzoylmalonate                                              459    448       Ethyl 2-[2-(1-pentadec-4,14-dienyl-                                           amino)benzoyl]acetoacetate                                   460    449       Ethyl 3-[1-(3,7,11-trimethyldodeca-2,6,-                                      10-trienyl)amino]benzoylacetate                              461    450       2-(2,3-Methanoheptylamino]benzoyl-                                            acetic acid                                                  462    451       3-[1-(6-Decylhept-6-enyl)amino]-                                              2-(methylsulfonyl)acetophenone                               463    452       2'-(Allylamino)-2-(phenylsulfonyl)-                                           acetophenone                                                 464    453       3'-(Proparygylamino)-2-(phenyl-                                               sulfinyl)acetophenone                                        465    454       3'[3-(2,3-Methanoheptylamino)benzoyl]-                                        2,4-pentanedione                                             466    455       Methyl 3-[3-(allylamino)benzoyl]-                                             propionate                                                   467    456       3-[2-(1-Pentadec-4-enylamino)benzoyl]-                                        propionic acid                                               ______________________________________                                    

EXAMPLE 468 Preparation of 2-[1-(2,3-methanoheptyl)amino]benzonitrile

2-Aminobenzonitrile (11.8 g.) and 1-iodo-2,3-methanoheptane (16.3 g.)are dissolved in hexamethylphosphoramide (100 ml.) and heated undernitrogen in an oil bath maintained at 120° C. for 22 hours. The reactionmixture is cooled to room temperature and water (100 ml.) is addedgradually. The mixture is then chilled in an ice bath. The precipitateseparated is filtered, washed thoroughly with water, and dried. It isthen washed repeatedly with hexane and dried. Recrystallization fromether-hexane affords 2-[1-(2,3-methanoheptyl)amino]benzonitrile as paleyellow crystals.

EXAMPLE 469 Preparation of 3-(allylamino)benzaldehyde

Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is addedwith stirring to a solution of 12.1 g. of 3-(allylamino)benzonitrileunder a nitrogen atmosphere. After addition is completed, the solutionis stirred for one hour. A solution of methanol in toluene (50 ml., 1:1)is added over 30 minutes and the mixture is poured into 500 ml.vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture isfiltered and the organic layer separated. The aqueous solution isextracted twice with toluene (100 ml.) and the combined organic layersare washed with aqueous sodium bicarbonate, dried over magnesiumsulfate, decolorized with charcoal, filtered and evaporated in vacuo togive a light yellow crystalline solid. The product is recrystallizedfrom dichloromethane/hexane giving colorless needles.

TABLE XIII

The following 2- or 3-(substituted-amino)benzonitriles are prepared bythe method of Example 468.

    ______________________________________                                        Example                                                                       No.       2- or 3-(Substituted-amino)benzonitrile                             ______________________________________                                        470       2-(Allylamino)benzonitrile                                          471       3-(1-Octadec-9-enylamino)benzonitrile                               472       2-(1-Pentadec-4-enylamino)benzonitrile                              473       3-(1-Tetradec-4-enylamino)benzonitrile                              474       2-(1-Pentadeca-4,14-dienylamino)benzonitrile                        475       3-[1-(3,7,11-Trimethyldodeca-2,6,10-trienyl)-                                 amino]benzonitrile                                                  476       2-[1-(6-Decylhept-6-enyl)amino]benzonitrile                         477       3-[4-(2,3-Methanoheptyl)amino]benzonitrile                          ______________________________________                                    

TABLE XIV

The following 2- or 3-(substituted-amino)benzaldehydes are prepared fromthe corresponding benzonitriles of Table XIII by the method of Example469.

    ______________________________________                                        Example                                                                       No.      2- or 3-(Substituted-amino)benzaldehydes                             ______________________________________                                        478      2-(Allylamino)benzaldehyde                                           479      3-(1-Octadec-9-enylamino)benzaldehyde                                480      2-(1-Pentadec-4-enylamino)benzaldehyde                               481      3-(1-Tetradec-4-enylamino)benzaldehyde                               482      2-(1-Pentadeca-4,14-dienylamino)benzaldehyde                         483      3-[1-(3,7,11-Trimethyldodeca-2,6,10-trienyl)-                                 amino]benzaldehyde                                                   484      2-[1-(6-Decylhept-6-enyl)amino]benzaldehyde                          485      3-[4-(2,3-Methanoheptyl)amino]benzaldehyde                           ______________________________________                                    

EXAMPLE 486 Preparation of 2,3-dihydroxypropyl2-(allylamino)phenylacetate

A solution of 7.34 g. of 2-(allylamino)phenylacetic acid, 4.80 g. of 25%aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50ml. of hexamethylphosphoramide is stirred for 24 hours at ambienttemperature, diluted with 100 ml. of ether and stirred for 5 days atambient temperature. The mixture is treated with water and extractedwith ether. The dried extracts are evaporated to yield2,3-dihydroxypropyl 2-(allylamino)phenylacetate.

EXAMPLE 487 Preparation of methyl 3-(allylamino)phenylacetate

A solution of 20.7 g. of 3-(allylamino)phenylacetic acid in 25 ml. ofhexamethylphosphoramide is added to a stirred mixture of 0.800 g. ofsodium hydride (57% in mineral oil) and 25 ml. ofhexamethylphosphoramide. The solution which forms after one hour istreated with 11.0 g. of methyl iodide and is then stirred at 25° C. for18 hours. Dilution with water followed by filtration affords a whitesolid which is crystallized from ethanol to yield methyl3-(allylamino)phenylacetate

EXAMPLE 488 Preparation of 3-hydroxypropyl 2-(allylamino)phenylacetate

A mixture of 2.25 g. of methyl 2-(allylamino)phenylacetate, 280 mg. of1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C.for 18 hours and then is partitioned between ether and 3% aqueous sodiumcarbonate solution. The ether layer is separated, dried, and evaporatedto yield 3-hydroxypropyl 2-(allylamino)phenylacetate.

EXAMPLE 489 Preparation of 2-ethoxyethyl 3-(allylamino)phenylacetate

A solution of 11.8 g. of 3-(allylamino)phenylacetic acid, 1.00 g. of2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml.toluene is stirred under reflux for 48 hours. The solution is treatedwith an additional 5.35 ml. of boron trifluoride etherate and refluxingis continued for 120 hours. Dilution with water and methylene chloridefollowed by filtration affords 2-ethoxyethyl3-(allylamino)phenylacetate.

EXAMPLE 490 Preparation of methyl 2-(allylamino)hydrocinnamate

A solution of 50.5 g. of 2-(allylamino)hydrocinnamic acid and 34.4 ml.of boron trifluoride etherate in 200 ml. of methanol is stirred underreflux for 44 hours, allowed to cool, and poured into 1.20 liters ofice-cold 5% aqueous sodium carbonate solution. The white solid iscollected by filtration and recrystallized from benzene-ethanol to yieldmethyl 2-(allylamino)hydrocinnamate.

EXAMPLE 491 Preparation of 1-(methoxycarbonyl)propyl3-(allylamino)hydrocinnamate

To a solution of 10.0 g. 3-(allylamino)hydrocinnamoyl chloridehydrochloride in 200 ml. methylene chloride is added dropwise a solutionof 3 g. methyl 2-hydroxybutyrate and 5 g. triethylamine in 100 ml.ether. After 17 hours stirring at room temperature, the precipitate iscollected and washed with several portions of ether. The ether solutionis washed with water, dried and evaporated to yield1-(methoxycarbonyl)propyl 3-(allylamino)hydrocinnamate as a white solid.

EXAMPLE 492 Preparation of 1-(ethoxycarbonyl)ethyl2-(allylamino)phenylacetate

To a warm mixture of 7 g. sodium 2-(allylamino)phenylacetate in 100 ml.ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours atreflux, the cooled solution is diluted with an equal volume of water andthe resultant precipitate is filtered. After washing with cold ethanoland drying, the product is crystallized from acetonitrile to yield1-(ethoxycarbonyl)ethyl 2-(allylamino)phenylacetate as colorlesscrystals.

EXAMPLE 493 Preparation of 1-carboxyethyl 3-(allylamino)phenylacetate

A flask containing 10.0 g. 3-(allylamino)phenylacetic acid, 3.3 g.lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene equippedwith a Soxhlet extractor charged with activated 4 Å Linde molecularsieves. The solution is refluxed for 24 hours during which time theSoxhlet extractor is charged twice more with fresh sieves. The hotsolution is filtered and left to cool, whereupon 1-carboxyethyl3-(allylamino)phenylacetate separates as off-white crystals.

EXAMPLE 494 Preparation of diethylO-[2-(allylamino)phenylacetyl]tartrate

A mixture of 2-[N-trifluoroacetyl-(allylamino)]phenylacetyl chloride and1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g.diethyl tartrate and refluxed for 24 hours. The hot solution isfiltered, the residue is washed with hot ether, and the solution isevaporated. After treatment with aqueous methanolic potassium carbonate,the product is precipitated by acidification, filtered, and dried.Crystallization from acetone yields diethylO-[2-(allylamino)phenylacetyl]tartrate as a white, crystalline solid.

EXAMPLE 495 Preparation of O-[3-(allylamino)phenylacetyl]malic acid

A warm solution of 3-[N-carbobenzyloxy-(allylamino]phenylacetyl chlorideand 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malicacid. An immediate precipitate forms, but the mixture is refluxed forone hour and filtered while hot. The solid is washed several times withhot ether, then the ether is evaporated to yield a white solid. Theproduct is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops.The catalyst is filtered, and the solution is evaporated. The residue iscrystallized from acetic acid to yieldO-[3-(allylamino)phenylacetyl]malic acid.

EXAMPLE 496 Preparation of 2-(ethoxycarbonyl)vinyl2-(allylamino)phenylacetate

To a mixture containing 4.3 g.1-[2-(N-t-butyloxycarbonyl-allylamino)phenylacetyl]imidazole 50 ml. 5 Nsodium hydroxide is added 3 g. ethyl 2-formyl acetate. The solution isvigorously stirred for 24 hours. The layers are separated, and thechloroform solution is washed once with 50 ml. 1 N sodium hydroxide. Thesolvent is evaporated and the residue is heated for 30 minutes at 40° C.in 50 ml. anhydrous trifluoracetic acid. The solvent is again evaporatedand the oil is crystallized from acetone to yield light yellow crystalsof 2-(ethoxycarbonyl)vinyl 2-(allylamino)phenylacetate.

TABLE XV

The following esters are prepared by the methods shown from thecarboxylic acids of Tables I, II, IV, VI, VIII and X or appropriatederivatives thereof obtained by the methods of Examples 441-445.

    ______________________________________                                        Example                                                                              Method of                                                              No.    Example   Ester                                                        ______________________________________                                        497    486       2,3-Dihydroxypropyl 2-(allylamino)-                                           phenylacetate                                                498    486       2,3-Dihydroxypropyl 3-(1-octadec-                                             9-enylamino)hydrocinnamate                                   499    486       2,3-Dihydroxypropyl 2-(1-pentadec-                                            4-enylamino)cinnamate                                        500    486       2,3-Dihydroxypropyl 3-(1-pentadec-                                            4,14-dienylamino)phenylpropiolate                            501    486       2,3-Dihydroxypropyl 2-[1-(3,7,11-                                             trimethyldodeca-2,6,10-trienyl-                                               amino]butyrate                                               502    487       Methyl 3-[1-(6-decylhept-6-enyl)                                              amino]phenylacetate                                          503    487       Methyl 2-[4-(2,3,methanoheptyl)-                                              amino]hydrocinnamate                                         504    487       Methyl 3-(1-pentadeca-4,14-dienyl-                                            amino)cinnamate                                              505    487       Methyl 2-(1-octadec-9-enylamino)-                                             phenylpropiolate                                             506    487       Methyl 3-[4-(allylamino)phenyl]-                                              butyrate                                                     507    488       2-Hydroxypropyl 2-(allylamino)-                                               phenylacetate                                                508    488       4-Hydroxybutyl 3-[1-(6-decylhept-                                             6-enyl)amino]hydrocinnamate                                  509    488       2-Hydroxypropyl 2-[1-(3,7,11-tri-                                             methyldodeca-2,6,10-trienyl)amino]-                                           cinnamate                                                    510    488       3-Hydroxypropyl 3-[4-(2,3-methano-                                            heptyl)amino)]phenylpropionate                               511    488       2-Hydroxyethyl 2-[1-(6-decylhept-                                             6-enyl)amino]phenylbutyrate                                  512    489       2-Methoxyethyl 3-(propargylamino)-                                            phenylacetate                                                513    489       2-Ethoxyethyl 2-(1-cyclopropyl-                                               methylamino)propionate                                       514    490       Methyl 3-(allylamino)hydrocinnamate                          515    490       Methyl 2-(3-cyclopropylpropyl-                                                amino)cinnamate                                              516    491       1-Methoxycarbonylpropyl 3-(1-pen-                                             tadec-4,14-dienylamino)hydrocin-                                              namate                                                       517    491       1-Ethoxycarbonylpropyl 2-[1-(6-                                               decylhept-6-enyl)amino]phenylpro-                                             pionate                                                      518    492       1-Ethoxycarbonylethyl 3-(1-pen-                                               tadec-4-enylamino)phenylpropionate                           519    493       1-Carboxyethyl 2-(1-octadec-9-eny-                                            lamino)phenylacetate                                         520    493       1-Carboxyethyl 3-[2-(2-methylcyclo-                                           propylethylamino]cinnamate                                   521    493       1-Carboxybutyl 2-(allylamino)-                                                phenylpropionate                                             522    493       1-Carboxyethyl 4-[3-(1-pentadec-                                              4-ethylamino)phenyl]butyrate                                 523    494       Diethyl O-[2-(1-pentadec-4,14-                                                dienylamino)phenylacetyl]tartrate                            524    495       O-[3-(Allylamino)benzoyl]malic                                                acid                                                         525    495       O-[2-(cyclopropylmethylamino)-                                                benzoyl]malic acid                                           526    496       2-(Ethoxycarbonyl)vinyl 3-(but-                                               2-enylamino)hydrocinnamate                                   527    496       2-(Ethoxycarbonyl)vinyl 2-(allyl-                                             amino)cinnamate                                              528    496       2-(Ethoxycarbonyl)vinyl 3-(tetra-                                             dec-4-amino)propiolate                                       529    496       2-(Ethoxycarbonyl)vinyl 4-[2-                                                 (1-octadec-9-enylamino)phenylbu-                                              tyrate                                                       ______________________________________                                    

EXAMPLE 530 Preparation of 2-(pentadec-4-enylamino)benzhydroxamic acid

To a suspension of 2-(pentadec-4-enylamino)benzoic acid (44 g.) in glyme(350 ml.) and pyridine (70 ml.) at 0° C. is added trifluoroaceticanhydride (67 ml., 100 g.) at such a rate as to maintain the temperatureat 20°-30° C. The resulting solution is stirred at 10°-15° C. for 2hours, then diluted with ether (499 ml.), cooled in an ice-bath and ice(100 gm.) is added. The mixture is stirred vigorously at ambienttemperature for 1 hours. The acqueous layer is extracted with ether andthe combined ether extracts are washed with water, brine, dried oversodium sulfate and concentrated in vacuo to provide 57 g. of2-[N-trifluoroacetyl-N-(pentadec-4-enyl)amino]benzoic acid as an oilthat solidifies upon standing.

The N-trifluoracetyl derivative (57 g.) is dissolved in thionyl chloride(300 ml.) and refluxed for 3 hours. After cooling, the mixture isdiluted with toluene and concentrated in vacuo. The residue is dilutedagain with hot toluene and filtered. The toluene is concetrated in vacuoto provide 61 g. of2-[N-trifluoroacetyl-N-(pentadec-4-enyl)amino]benzoyl chloride as anoil.

To a stirred solution of hydroxylamine hydrochloride (16 g.) in pyridine(75 ml.) and dichloromethane (35 ml.) is added dropwise the previouslyprepared benzoyl chloride derivative (11.5 g.) in dichloromethane (20ml.). After 1 hour, the mixture is diluted with water and extracted withether. The combined organic extract is then washed with water, brine,dried with sodium sulfate and contrated in vacuo to afford2-[N-trifluoroacetyl-N-(pentadec-4-enyl)amino]benzhydroxamic acid as anoil.

A portion of this oil (0.9 g.) is dissolved in ethanol (20 ml.), 1 Nsodium hydroxide solution is added, and the mixture is stirred atambient temperature. The mixture is stirred at ambient temperature. Themixture is chilled and filtered to provide a white solid that is washedwith ethanol. The white solid is recrystallized from hot ethanol toprovide 2-(pentadec-4-enylamino)benzhydroxamic acid.

EXAMPLE 531 Preparation of Esters

Treatment of the acids of Examples 1-317 and 321-358 with trifluoraceticanhydride to provide the N-COCF₃ derivative, followed by treatment withthionyl chloride to provide the N-COCF₃ acid chloride, followed bytreatment with one of the following alcohols, followed by removal of theN-COCF₃ group with sodium hydroxide by the method of Example 530provides the corresponding ester of the starting acid.

Alcohols: benzyl alcohol, p-fluorobenzyl alcohol, p-bromobenzyl alcohol,p-chlorobenzyl alcohol, p-methoxybenxyl alcohol, m-chlorobenzyl alcohol,p-carboxybenzyl alcohol, phenol, p-fluorophenol, p-bromophenol,p-chlorophenol, p-methoxyphenol, p-carboxyphenol, 4-cyanophenol,3-hydroxypyridine, 2-chloro-3-hydroxypyridine,5-carboxy-3-hydroxypyridine.

EXAMPLE 532 Preparation of Amides

Treatment of the acids of Examples 1-317 and 321-358 withtrifluoroacetic anhydride to provide the N-COCF₃ derivative, followed bytreatment with thionyl chloride to provide the N-COCF₃ acid chloride,followed by treatment with one of the following amines, followed byremoval of the N-COCF₃ group with sodium hydroxide by the method ofExample 530 provides the corresponding amide of the starting acid.

Amines: β-alanine, allylamine, allylcyclohexylamine, aminoacetonitrile,α-aminoacetophenone, 2-amino-1-butanol, 3-aminobutyric acid,4-aminobutyric acid, 1-amino-1-cyclopentanemethanol,2-amino-5-diethylaminopentane, N-(2-aminoethyl)morpholine,N-(2-aminoethyl)piperazine, N-(2-aminoethyl)piperidine,2-amino-2-ethyl-a,3-propanediol, 2-(2-aminoethyl)pyridine,N-(2-aminoethyl)pyrrolidine, DL-4-amino-3-hydroxybutyric acid,5-aminolevulinic acid, aminoethanesulfonic acid,p-aminoethylbenzenesulfonamide, 2-amino-3-methyl-1-butanol,aminomethylcyclobutane, 4-(aminomethyl)cyclohexanecarbonitrile,1-aminoethyl-1-cyclohexanol, aminomethylcyclopropane,4-(aminomethyl)piperidine, 2-amino-2-methyl-1,3-propanediol,2-amino-2-methyl-1-propanol, 2-(aminomethyl)-2-propanol,2-aminomethylpyridine, 3-aminomethylpyridine, 4-aminomethylpyridine,2-amino-1-phenyl-ethanol, 2-amino-3-phenyl-1-propanol,3-amino-3-phenylpropionic acid, 3-amino-1,2-propanediol,1-amino-2-propanol, N-(3-aminopropyl)diethanolamine,N-(3-aminopropyl)morpholine, 1-(3-aminopropyl)-2-pipecoline,N-(3-aminopropyl)-2-pyrrolidinone, 5-aminovaleric acid,bis-(2-ethanolethyl)amine, bis-(2-methylallyl)amine,p-bromophenethylamine, 3-bromopropylamine hydrobromide, n-butylamine,sec-butylamine, tert-butylamine, 2-chlorobenzylamine,3-chlorobenzylamine, 5-chlorobenzylamine, 2-chloroethylamine,3-chloropropylamine, cyclobutylamine, cycloheptylamine,1,3-cyclohexanebis(methylamine), cyclohexanemethylamine,cyclohexylamine, cyclopentylamine, cyclopropylamine,3-(di-n-butylamino)propylamine, 1,5-dimethylhexylamine,α,4-dimethyl-3-hydroxyphenethylamine, 1,1-dimethylpropargylamine,1,2-dimethylpropylamine, 1,2-diphenylethylamine, ethylamine,ethyl-3-aminobutyrate, ethyl-4-aminobutyrate, 2-(ethylamino)ethanol,1-ethylpropylamine, 1-ethynylcyclohexamine, m-fluorobenzylamine,p-fluorobenzylamine, 2-fluoroethylamine, furfurylamine, n-heptylamine,isoamylamine, isopropylamine, m-methoxybenzylamine,p-methoxybenzylamine, 2-methoxyethylamine, o-methoxyphenthylamine,p-methoxyphenethylamine, N-methyl-β-alanine-nitrile, 2-methylallylamine,methylamine, methylaminoacetonitrile, 2-(methylaminoethanol,2-methylbenzylamine, 3-methylbenzylamine, 4-methylbenzylamine,4-methylbenzylamine, 1-methylbutylamine, 4-methylcyclohexylamine,1-norepinephrine, 4-phenylbutylamine, 1-phenylcyclopropanemethylaine,trans-2-phenylcyclopropylamine, D(-)-α-phenylglycinol,2phenylglycinonitrile, phenylpropanolamine, 3-phenyl-a-propylamine,monopropargylamine, propylamine, taurine, tetrahydrofurfurylamine,1,2,3,4-tetrahydro-1-naphthylamine, 2-(p-tolyl)ethylamine,m-aminobenzoic acid, p-aminobenzoic acid, o-aminobenzyl alcohol,p-aminobenzyl alcohol, 3,5-dimethylpiperidine, 2-ethylpiperidine,3-hydroxypiperidine, 4-hydroxypiperidine, 2-iminopiperidine,isonipecotamide, isonipecotic acid,methyl-4-oxo-3-piperidinecarboxylate, 2-methylpiperidine,3-methylpiperidine, 4-methylpiperidine, nipecotamide,4-phenylpiperidine, 4-phenyl-1,2,3,5-tetrahydropyridine, pipecolinicacid, piperidine, 2-piperidineethanol, 2-piperidinemethanol,3-piperidinemethanol, 4-piperidinopiperidine, 4-piperidine,1,2,3,6-tetrahydropyridine, 2,2,6,6-tetramethylpiperidine,2,2,6,6-tetramethyl-4-piperidinol, 2,2,6,6-tetramethyl-4-piperidone,4,4-trimethylenedipiperidine, 2-methylpiperidine, 3-methylpiperidine,4-methylpiperidine, 4-phenylpiperidine, piperidine, morpholine,hexamethyleneimine, heptamethyleneimine, pentamethyleneimine,pyrrolidine, N-methylpiperazine, dl-alanine, hydrazine,N-acetylhydrazine, dl-valine, Δ³ -piperidine, dl-leucine,2-aminoisobutyric acid.

EXAMPLE 533 Preparation of N-[3-(9-Octadecenylamino)benzoyl]benzamide

Sodium hydride (1.0 g., 50% dispersion in mineral oil) is washed withhexane three times under nitrogen. To the dry sodium hydride is added 5ml. of freshly distilled tetrahydrofuran. To this suspension is added asolution of 2.4 g. of benzamide in 5 ml. of tetrahydrofuran. Aftercomplete reaction (30 min.), a solution of 0.9 g.3-[N-(trifluoracetyl-N-(9-octadecenyl)amino]benzoyl chloride (Example530) in 3 ml. of tetrahydrofuran is added. After stirring at ambienttemperature for 1 hour, the reaction mixture is poured into water andextracted twice with ether. The ether extracts are washed with water,brine, dried with sodium sulfate, and concentrated in vacuo. The residueis recrystallized from ether-acetonitrile (1:1) to provideN-{3-[N-trifluoracetyl-N-(9-octadecenyl)amino]benzoyl}benzamide.

The N-trifluoroacetyl compound is in turn treated with ethanol and 1 Nsodium hydroxide and the mixture is stirred at ambient temperature for 6hours. Chilling and filtration affords a white solid which isrecrystallized from ethanol to yieldN-[3-(9-octadecenylamino)benzoyl]benzamide.

EXAMPLE 534 Preparation of N-[2- or 3-(substituted amino)benzoyl orphenylacetyl]benzamides

Treatment of the N-COCF₃ acid halides (prepared by the method of Example530 from the corresponding acids of Examples 1-317 and 321-358) withbenzamide and sodium hydride followed by removal of the N-COCF₃ group bythe method of Example 533 is productive of the corresponding benzamides.

EXAMPLE 535 Preparation of2-(4-pentadecenylamino)-N-(phenylsulfonyl)benzamide

A solution of 31.4 g. of benzenesulfonamide in 250 ml. of drydimethylacetamide is added dropwise, with stirring and cooling, to asuspension of 5.5 g. of sodium hydride in 100 ml. of drydimethylacetamide over 30 minutes at room temperature. Stirring iscontinued for a further 30 minutes. In the meantime, a mixture of 36.2g. of 2-(4-pentadecenylamino)benzoic acid in 1200 ml. of methylenechloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride isrefluxed for 1 hour and 15 minutes. The solution is evaporated to an oilwhich is co-evaporated twice with added dioxane to remove excess thionylchloride. To the resulting oily residue of2-(4-pentadecenylamino)benzoyl chloride hydrochloride is added, in oneportion, the previously prepared mixture of sodium benzenesulfonamide indimethylacetamide. The mixture is stirred for 30 minutes, withoutcooling, and is then filtered through a bed of diatomaceous earth. Thefiltrate is poured into 2 l. of water, and 250 ml. of saturated sodiumchloride solution is added to coagulate the precipitate. The mixture isfiltered and the product is washed with water and partially air dried.The product is dissolved in methylene chloride, the mixture is filteredthrough diatomaceous earth, and brine is added to break the emulsion.The layers are separated, the organic phase is dried over anhydroussodium sulfate and filtered through a bed of 300 g. of hydrous magnesiumsilicate. The product is eluted with an additional 3 l. of methylenechloride. The first approximately 1 l. of filtrate is set aside and theremainder is evaporated to dryness. The residue is crystallized threetimes from toluene and the product is dried in the Abderhalden at 65° C.to provide the title compound as colorless crystals.

EXAMPLE 536 Preparation of 2- or 3-(substitutedamino)-N-(sulfonyl)benzamides or phenylacetamides

Treatment of the acid chloride hydrochloride (prepared from thecorresponding carboxylic acids of Examples 1-317 and 321-358 by theprocedure of Example 539 with the following sulfonamides by theprocedure of Example 535 is productive of the corresponding 2- or3-(substituted amino)-N-(sulfonyl)benzamide or phenylacetamides. Thesulfonamide starting materials are benzenesulfonamide,methanesulfonamide, p-methylphenylsulfonamide, p-nitrophenylsulfonamide,p-chlorophenylsulfonamide.

EXAMPLE 537 Preparation of N-trifluoroacetyl-2 or3-(4-tetradecenylamino)benzoyl chloride

A stirred, ice-cold suspension of 9 g. (24.9 m moles) 2- or3-(4-tetradecenylamino)benzoic acid in 100 ml. dimethoxy ethane and 16ml. pyridine is treated with 18 ml. trifluoroacetic anhydride. Thesolution is stirred at 0° C. for 30 minutes at room temperature. Thesolution is diluted with 300 ml. ether and 100 g. ice. After stirringvigorously for 15 minutes, the phases are separated, the ether solutionis washed with brine, dried and evaporated to a white amorphous solid.

To 9.2 g. of the above product in 30 ml. methylene chloride and 0.5 ml.dimethylformamide is added 5.7 ml. thionyl chloride. After 20 hours atreflux, the solvents are evaporated to yield the product as a lightyellow, mobile oil.

EXAMPLE 538 Preparation of N-carbobenzyloxy-2 or3-(4,14-pentadecadienylamino)benzoyl chloride

To 15 g. of 2- or 3-(4,14-pentadecadienylamino)benzoic acid in 200 ml.warm chloroform is added 15 g. sodium carbonate in 150 ml. water. To thevigorously stirred mixture is added 10 g. carbobenzoyl chloride. After 2hours stirring at 40° C., the layers are separated, the chloroform layeris washed three times with 1 N hydrochloric acid, dried, and the solventevaporated to yield an oil. The oil is dissolved in 300 ml. toluene,treated with 15 ml. of thionyl chloride, and the solution is refluxedfor 5 hours. The solvents are evaporated and the residue is dissolvedthree times in toluene, evaporating each time to yield a viscous, orangeoil.

EXAMPLE 539 Preparation of 2- or 3-(4-tetradecenylamino)benzoyl chloride

A cold solution of 25 g. 2- or 3-(4-tetradecenylamino)benzoic acid in500 ml. dimethoxyethane-methylene chloride (4:1) is prepared and dryhydrochloric acid is bubbled through the solution until no moreprecipitate forms.

The solution is treated with 25 ml. thionyl chloride and refluxed untilall of the precipitate has dissolved. The solvents are evaporated toyield an orange, semi-crystalline mass.

In an analogous manner, 2- or 3-(4-tetradecenylamino)phenylacetylchloride is obtained from the corresponding phenylacetic acid.

EXAMPLE 540 Preparation of N-[2-(4-tetradecenylamino)benzoyl]alanine

A solution pf 4.75 g. of N-trifluoroacetyl-2-(tetradecenylamino)benzoylchloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treatedwith 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hotsolution is filtered, the residue is washed with hot ether, and thesolvent is evaporated from the combined filtrate and washings. Aftertreatment of the residue with aqueous methanolic potassium carbonate,the product is precipitated by acidification, filtered and dried.Crystallization from acetone yields the product as a white, crystallinesolid.

EXAMPLE 541 Preparation of 1-{3-[N-(t-butyloxycarbonyl)-N-(4-tetradecenylamino)benzoyl}imidazole

A solution of 10 g. of 3-(4-tetradecenylamino)benzoic acid in 100 ml.dioxane is treated with 4.0 g. of t-butylazidoformate and 10 ml.pyridine. After stirring at room temperature for 18 hours, the protectedamido-acid is precipitated from solution by addition of 150 ml. ofwater. The product is collected and thoroughly dried. The curde productis dissolved in 200 ml. of a mixture consisting of methylenechloride/dimethoxy ethane/pyridine (1:4:1), and to this is added 5.4 g.of 1,1'-carbonyldiimidazole. The solution is stirred overnight at roomtemperature and the solvents are evaporated to yield the title compoundas a thick orange oil.

EXAMPLE 542 Preparation of 1-[2- or3-(4,14-pentadecadienylamino)benzoyl]piperidine

To a warm solution of 2- or3-[N-carbobenzoyloxy-4,14-pentadecadienylamino]benzoyl chloride and 1.3g. of triethylamine in 100 ml. ether is added 1.2 g. of piperidine. Animmediate precipitate forms, but the mixture is refluxed for one hourand filtered while hot. The solid is washed several time with hot ether,then the ether is evaporated from the combined filtrate and washings toyield a white solid. The product is dissolved in tetrahydrofuran (100ml.) and hydrogenated over 600 mg. 10% palladium on carbon at 20 psiuntil hydrogen uptake stops. The catalyst is filtered. The solution isevaporated, and the residue is crystallized from acetic acid to yieldthe title compound as a crystalline mass.

Treatment of a corresponding 2- or 3-(substituted-amino)phenylacetylchloride in an analagous manner yields the corresponding piperidide.

EXAMPLE 543 Preparation of 1-[2- or3-(4,14-pentadecadienylamino)benzoyl]pyrrolidine

A solution of 6.0 g. of 2- or3-[N-carbobenzyloxy-N-(4,14-pentadecadienylamino)]benzoyl chloride and1.2 g. triethylamine in 100 ml. warm ether is treated with 1.1 g. ofpyrrolidine. After 1 hour at reflux, the precipitate is filtered off andwashed with warm ether. After evaporation of the combined filtrate andwashings to dryness, the residue is dissolved in 50 ml. 30% hydrobromicacid in acetic acid and warmed at 50° C. for 2 hours. The solvents areevaporated and the product is partioned between methylene chloride andwater. The layers are separated and the methylene chloride isevaporated. The residue is crystallized from acetone to yield colorlesscrystals.

Treatment of a corresponding 2- or 3-(substituted amino)phenylacetylchloride in an analogous manner yields the corresponding pyrolidide.

EXAMPLE 544 Preparation of O-[2-(4,14-pentadecadienylamino)benzoyl]malicacid

A warm solution of N-carbobenzyloxy-2-(4,14-pentadecadienylamino)benzoylchloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g.malic acid. An immediate precipitate forms, but the mixture is refluxedfor one hour and filtered while hot. The solid is washed several timeswith hot ether, then the ether is evaporated to yield a white solid. Theproduct is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops.The catalyst is filtered. The solution is evaporated and the residue iscrystallized from acetic acid to yield the title compound as whitecrystals.

EXAMPLE 545 Preparation of N-[2- or3-(4-tetradecenylamino)benzoyl]alanine

A solution of 4.75 g. of N-trifluoroacetyl-2- or3-(4-tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester andrefluxed for 24 hours. The hot solution is filtered, the residue iswashed with hot ether, and the combined filtrate and washings areevaporated. After treatment of the residue with aqueous methanolicpotassium carbonate, the product is precipitated by acidification,filtered and dried. Crystallization from acetone yields the product awhite, crystalline solid.

Treatment of a corresponding 2- or 3-(substituted amino)phenylacetylchloride in an analagous manner yields the corresponding alanines.

EXAMPLE 546 Preparation of 4-chlorophenyl2-(4-tetradecenylamino)benzoate

To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500ml. methylene chloride is added 10.4 g. 2-(4-tetradecenylamino)benzoylchloride hydrochloride in 250 ml. methylene chloride. After four hoursat reflux, the solution is cooled, washed with water and dilutephosphoric acid, and dried. After passing the solution through a columnof alumina, the solvent is evaporated and the residue is crystallizedfrom diisopropyl ether.

EXAMPLE 547 Preparation of N-[2-(4-tetradecenylamino)benzoyl]-2-aminoethanesulfonic acid

To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylaminein 22.5 ml. of water is added 5.55 g. ofN-{2-[2,2,2-trifluoro-N-(4-tetradecenyl)acetamido]benzoyloxy}succinimideas a solution in 45 ml. of ethanol. After 24 hours, the mixture istreated with 20 ml. of 2.0 M sodium hydroxide and 25 ml. of water. Afterstirring for 10 minutes, the mixture is acidified with dilutehydrochloric acid, and the crude product is collected by filtration.Recrystallization affords the title compound as a white solid.

EXAMPLE 548 Preparation of3-[3-(4-pentadecenylamino)benzoyl]-4-carboethoxythiazolidine

One-tenth mole of 3-(4-pentadecenylamino)benzoyl chloride hydrochloridein methylene chloride is added to a solution of 0.1 mole of ethylthiazolidine-4-carboxylate in chloroform containing two equivalents oftriethylamine. After 5 hours at 20° C. the solution is filtered andevaporated to a white solid which is recrystallized from acetonitrile.

EXAMPLE 549 Preparation of3-[3-(4-pentadecenylamino)benzoyl]-4-carboxythiazolidine

By means of the alkaline hydrolysis method of Example 2 the ethyl esterof Example 548 is converted to the subject carboxylic acid. This acid isalso prepared using the procedure of Example 548 except that theacylation of the thiazolidine-4-carboxylic acid is carried out inaqueous acetone sodium bicarbonate solution.

EXAMPLE 550 Preparation of N-[2- or3-(4-pentadecenylamino)benzoyl]glycine

A mixture of 26.4 g. of ethyl N-[2- or3-(4-pentadecenylamino)benzoyl]glycinate, 110 ml. of 1 N sodiumhydroxide solution, and 100 ml. of ethanol is stirred at ambienttemperature for 2 hours and then partially evaporated. The gaseoussolution is washed with diethyl ether, acidified with 6 N hydrochloricacid, and filtered. The white solid is dried in vacuo and recrystallizedfrom acetone.

Treatment of a corresponding 2- or 3-substituted-aminophenylacetylchloride in an analogous manner yields the corresponding glycine.

EXAMPLE 551 Preparation ofN-[3-(4-pentadecenylamino)benzoyl]-2,3-dihydroxypropylamine

To a mixture containing 4.3 g. of[N-(t-butyloxycarbonyl)-3-(4-pentadecenylamino)benzoyl]imidazole, 50 ml.of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of3-amino-1,2-propanediol. The mixture is vigorously stirred for 24 hours,the layers are separated, and the chloroform solution is washed oncewith 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and theresidue is heated for 30 minutes at 40° C. in 50 ml. of anhydroustrifluoroacetic acid. The solvent is again evaporated and the resultingoil is crystallized from acetone to yield the product as light yellowcrystals.

EXAMPLE 552 Preparation ofN-(3-bromopropyl)-2-(4-tetradecenylamino)benzamide

To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. ofglyme at 3° C. is added a solution of 23.9 g. of2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 65 ml. ofglyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with1,2-dimethoxyethane. The solution is warmed to reflux and 0.2 g. of4-dimethylaminopyridine is added. The solution is heated for four hoursand cooled overnight. The solid is removed and the mother liquor dilutedwith 200 ml. of water to yield a solid which is crystallized fromcyclohexane and recrystallized from acetonitrile to yield the product.

EXAMPLE 553 Preparation of2-[3-(4-tetradecenylamino)phenyl]-5,6-dihydro-[4H]-1,3-oxazine

To 0.4 g. of sodium hydride in 100 ml. of 1,2-dimethoxyethane is added2.14 g. of N-(3-bromopropyl)-3-(4-tetradecenylamino)benzamide and 12 ml.of triethylamine. The turbid solution is heated to reflux for 20 hours.The solution is diluted with 100 ml. of water and cooled overnight. Thesolid is collected, washed with water, crystallized from cyclohexane,and recrystallized from acetonitrile to yield the product.

EXAMPLE 554 Preparation of 2-[2-(4-tetradecenylamino)phenyl]oxazoline

To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of1,2-dimethoxyethane are added simultaneously solutions of 31 g. of2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 60 ml. of1,2-dimethoxyethane and 50 cc. of triethylamine (dropwise). Uponaddition of 0.5 g. of 4-dimethylaminopyridine the mixture is stirred atroom temperature overnight. The solution is refluxed for one hour andfiltered. The solid is oven dried and partitioned between methylenechloride and water. The layers are separated and the organic phase driedover magnesium sulfate. The organic layer is concentrated and theresidue collected and crystallized from cyclohexane and recrystallizedfrom acetonitrile to yield the product.

EXAMPLE 555 Preparation of tetrahydropyranyl3-(4-tetradecenylamino)benzoate

A mixture of 7 g. 3-(4-tetradecenylamino)benzoic acid, 2 g. dihydropyranand 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene isstirred at room temperature for 20 hours. The solution is washed withsaturated sodium bicarbonate, dried, and evaporated. The residue iscollected and crystallized from methylcyclohexane to yield the productas white crystals.

EXAMPLE 556 Preparation of 3-pyridyl 2-(4-tetradecenylamino)benzoate

A 6 g. sample of 2-(4-tetradecenylamino)benzoic acid and 2.7 g.1,1'-carbonydiimidazole in 50 ml. dry tetrahydrofuran is stirred for 2hours. Then 1.58 g. 3-hydroxypyridine and a trace of sodium hydridecatalyst is added and the reaction is refluxed for 3 hours. The solutioncooled, filtered, and evaporated. The product is crystallized fromisopropanol.

I claim:
 1. An acid containing the organic radical(2,3-methanohept-4-ylamino) selected from the group consisting of3-(2,3-methanohept-4-ylamino)benzoic acid,3-[3-(2,3,-methanohept-4-ylamino)phenyl]propionic acid,4-[3-(2,3,-methanohept-4-ylamino)phenyl]butyric acid,3-[3-(2,3-methanohept-4-ylamino)phenyl]acrylic acid,3-(2,3-methanohept-4-ylamino)phenylpropionic acid,3-(2,3,-methanohept-4-ylamino)benzoylacetic acid,3-[3-(2,3,-methanohept-4-ylamino)benzoyl]propionic acid, and2-(2,3,-methanohept-4-ylamino)benzoylacetic acid.
 2. A compoundcontaining the organic radical (2,3-methanohept-4-ylamino) selected fromthe group consisting of 3-(2,3-methanohept-4-ylamino)benzaldehyde,3-(2,3-methanohept-4-ylamino)acetophenone, and2'-(2,3-methanohept-4-ylamino)-2-(methylsulfonyl)acetophenone.
 3. Anester containing the organic radical (2,3-methanohept-4-ylamino)selected from the group consisting of2-[2-(2,3-methanohept-4-ylamino)benzoyl]acetoacetate and3-(2,3,-methanohept-4-ylamino)benzoylmalonate.
 4. The compound accordingto claim 1, 3-(2,3-methanohept-4-ylamino)benzoic acid.
 5. The compoundaccording to claim 1, 3-[3-(2,3,-methanohept-4-ylamino)phenyl]propionicacid.
 6. The compound according to claim 1,4-[3-(2,3-methanohept-4-ylamino)phenyl]butyric acid.
 7. The compoundaccording to claim 1, 3-[3-(2,3,-methanohept-4-ylamino)phenyl]acrylicacid.
 8. The compound according to claim 1,3-(2,3-methanohept-4-ylamino)phenylpropionic acid.
 9. The compoundaccording to claim 1, 3-(2,3-methanohept-4-ylamino)benzaldehyde.
 10. Thecompound according to claim 1,3-(2,3-methanohept-4-ylamino)acetophenone.
 11. The compound according toclaim 1, 3-(2,3,-methanohept-4-ylamino)benzoylacetic acid.
 12. Thecompound according to claim 2, ethyl2-[2-(2,3-methanohept-4-ylamino)benzoyl]acetoacetate.
 13. The compoundaccording to claim 2, diethyl3-(2,3,-methanohept-4-ylamino)benzoylmalonate.
 14. The compoundaccording to claim 1,2'-(2,3-methanohept-4-ylamino)-2-(methylsulfonyl)acetophenone.
 15. Thecompound according to claim 1,3-[3-(2,3,-methanohept-4-ylamino)benzoyl]propionic acid.
 16. Thecompound according to claim 1,2-(2,3,-methanohept-4-ylamino)benzoylacetic acid.